Anti-PD-1 After Autologous Transplant for Multiple Myeloma 1

Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 1

TITLE: Phase 2 Multi-center Study of Anti-Programmed-Death-1 [anti-PD-1] during Lympho- penic State After High-Dose Chemotherapy and Autologous Hematopoietic Stem Cell Transplant [HDT/ASCT] for Multiple myeloma

IND NUMBER: 125767

EudraCT NUMBER:

Institution Name: University of Michigan (Primary Site) Medical College of Wisconsin

Principal Investigator Information:

Name: Attaphol Pawarode, M.D. Assistant Professor of Internal Medicine Blood and Marrow Transplantation Program Division of Hematology/Oncology, Department of Internal Medicine University of Michigan Medical School

Address: University Hospital South, BMT Program, Room F4811 1500 E. Medical Center Drive Ann Arbor, MI 48109, SPC 5271 Phone: 734-936-8785; Fax: 734-232-4484 Email Address: [email protected]

University of Michigan Co-Investigators:

Pavan Reddy, M.D., Professor of Translational Oncology John Magenau, M.D. Assistant Professor of Internal Medicine Mary Riwes, D.O. Assistant Professor of Internal Medicine Brian Parkin, M.D. Clinical Lecturer Vedran Radojcic, MD, Clinical Lecturer Blood and Marrow Transplantation Program Erica Campagnaro, M.D., Associate Professor of Hematology/Oncology Craig Cole, M.D., Assistant Professor of Hematology/Oncology Division of Hematology/Oncology

Steven K. Lundy, Ph.D., Research Assistant Professor Division of Rheumatology

Medical College of Wisconsin Investigators:

Anita D'Souza, M.D., M.S. Assistant Professor of Medicine (Institutional PI) Marcelo C. Pasquini, M.D., M.S., Professor of Medicine Parameswaran Hari, M.D., M.S., Professor of Medicine Timothy Fenske, MD Associate Professor of Medicine Wael Saber,MD, MS, Associate Professor of Medicine William Drobyski, MD, Professor of Medicine

Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 2

Douglas Rizzo, MD, MS, Professor of Medicine Mehdi Hamadani, MD, Associate Professor of Medicine Mary Horowitz, MD, MS, Professor of Medicine Bronwen Shaw, MD, PhD, Professor of Medicine

Bryon Johnson, PhD, Professor of Pediatrics Blood and Marrow Transplant Program Hematology/Oncology Medical College of Wisconsin

Statistician: Thomas Braun, Ph.D., Professor of Biostatistics Department of Statistics, University of Michigan

Study Coordinators: Jennifer Lay-Luskin, CCRP Nancy McCullough, CCRP

Address NCRC, Oncology-Clinical Trials Support Unit, 2800 Plymouth Rd., Bldg. 300, Ann Arbor, MI 48109-2800 Phone: 734-615-6872, 734-232-0758, 734-936-8538; Fax: 734-232-0744 E-mail: [email protected], [email protected], [email protected]

Data Managers: Kathleen Granlund, CCRP, Karen Dziubek, BS, CCRP Multi-Site Clinical Research Project Managers

Address: NCRC, Oncolocy-Clinical Trials Support Unit, 2800 Plymouth Rd., Bldg. 300, Ann Arbor, MI 48109-2800 Phone: 734-936-0563, 734-763-2968; Fax: 734-232-0744 E-mail: [email protected], [email protected]

Contracting Person: Name: Tricia Haynes, Assistant Project Representative Address: ORSP, Wolverine Tower, Room 1024, 3003 South State Street, Ann Arbor, MI 48109-1274 Phone no 734-615-8383 Fax no 734-763-4053; 764-8510 Email Address: [email protected]

Protocol version date: 03/09/2017

Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 3

TABLE OF CONTENTS TITLE PAGE 1 TABLE OF CONTENTS 3 1 STUDY SUMMARY 4 2 STUDY SYNOPSIS 4 3 OBJECTIVE(S) & HYPOTHESIS(ES) 5 4 BACKGROUND & RATIONALE 6 5 METHODOLOGY 5.1 ENTRY CRITERIA 18 5.1.1 DIAGNOSIS/CONDITION FOR ENTRY INTO THE TRIAL 18 5.1.2 SUBJECT INCLUSION CRITERIA 19 5.1.3 SUBJECT EXCLUSION CRITERIA 20 5.2 INCLUSION CRITERIA TO INITIATE ON MK-3475 21 5.3 TREATMENTS 23 5.3.1 STANDARD MULTIPLE MYELOMA TREATMENT 23 5.3.2 MK-3475 TREATMENT 24 TREATMENT SCHEMA 24 5.3.3 STANDARD TRANSPLANTATION DRUGS 24 5.3.4 STUDY DRUG: MK-3475 28 5.4 CONCOMITANT MEDICATIONS/VACCINATIONS 31 5.5 RESCUE MEDICATIONS & SUPPORTIVE CARE 33 5.6 SUBJECT WITHDRAWAL/DISCONTINUATION CRITERIA 37 5.7 SUBJECT REPLACEMENT STRATEGY 38 5.8 CLINICAL CRITERIA FOR EARLY STUDY TERMINATION 39 5.9 PLANS TO DISCONTINUE THE DEVELOPMENT OF THE MK-3475 39 5.10 DEFINITION OF ENDPOINTS 5.10.1 SAFTY END POINTS 39 5.10.2 EFFICACY END POINTS 40 5.10.3 CORRELATIVE STUDIES 40 6 STUDY FLOW CHART 43 7 STUDY PROCEDURES 7.1 STUDY PROCEDURES 47 7.1.1 ADMINISTRATIVE PROCEDURES 47 7.1.2 CLINICAL PROCEDURES/ASSESSMENTS 48 7.1.3 LABORATORY PROCEDURES/ASSESSMENTS 50 7.1.4 OTHER PROCEDURES 50 7.1.5 STUDY VISIT REQUIREMENTS 50 7.1.6 STUDY DEFINITIONS 51 7.2 ASSESSING AND RECORDING ADVERSE EVENTS 52 8 STATISTICAL ANALYSIS PLAN 8.1 STATISTICAL ANALYSIS PLAN SUMMARY 61 8.2 STATISTICAL ANALYSIS PLAN 61 8.3 STOPPING RULES 62 9 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES 63 10 ADMINISTRATIVE AND REGULATORY DETAILS 64 11 ADMINISTRATIVE AND LEGAL OBLIGATIONS 65 12 LIST OF REFERENCES 68 13 APPENDICES 77

Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 4

1.0 STUDY SUMMARY

Abbreviated Title Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma Trial Phase 2 Clinical Indication Multiple myeloma patients with inadequate response from prior therapy Trial Type Multi-Center Phase 2 Type of control None Route of administration Intravenous Trial Blinding None Treatment Groups Single Treatment Group Number of trial subjects A total of 50 subjects Estimated duration of Study 2 years Duration of Participation 7 months (Enrollment to End-of-Study Safety Evaluation)

2.0 STUDY SYNOPSIS

2.1 Study Design Phase 2 Multi-center Single-arm Study

2.2 Treatments 1. Standard Multiple Myeloma Treatments 1.1 High-dose Melphalan and Autologous Stem Cell Transplantation High-dose melphalan 140-200 mg/m2 (<200 mg/m2 for age >70 years) 1.2 Post-transplant Maintenance Lenalidomide 5-15 mg/day, starting day 45-90 post-transplant

2. Study Treatment: 200 mg/day of MK-3475 will be administered every 3 weeks, starting day 14 post-transplant (or after engraftment) for a total of 9 doses or ~180 days after transplant. Treatment days are +/- 4 days flexible.

2.3 Treatment Diagram

Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 5

3.0 OBJECTIVE(S) & HYPOTHESIS(ES)

3.1 Primary Objectives & Hypothesis

Objectives:

(1) To investigate the feasibility (safety and tolerability) of the addition of anti-PD1 after high dose therapy and autologous hematopoietic stem cell transplant in patients with multiple myeloma.

(2) To investigate the efficacy of the addition of anti-PD1 after high dose therapy and autologous hematopoietic stem cell transplant in improving complete response (CR) conversion rate for patients with multiple myeloma

Hypothesis: The administration of anti-PD-1 during the lymphopenic state after high dose therapy and autologous hematopoietic stem cell transplant is safe and tolerable and will enhance recognition and eradication of multiple myeloma by the recovering immune system and will result in a higher CR conversion rate.

See Appendix 13.3 for the definition of complete response (CR).

3.2 Secondary Objective & Hypothesis

Objective: To investigate the efficacy of this strategy in improving other transplant outcomes especially 2- year progression-free and overall survival (PFS and OS).

Hypothesis: The intervention increases other transplant outcomes especially 2-year PFS among patients achieving CR by day 180.

See Section 5.10 for the definition of PFS and OS.

3.3 Exploratory Objectives

(1) To perform correlative studies of the effects of anti-PD-1 on T-cell and NK-cell function.

Hypothesis: Enhanced Th1-type and cytotoxic immune responses following anti-PD-1 treatment will correlate with prolonged remission, while relapse will correlate with reduced Th1 response or increased regulatory immune response.

(2) To measure immune cell phenotypes in the autologous graft tissue being transplanted.

Hypothesis: Remission and relapse rates will correlate with differences in cell types present in the graft

Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 6

4.0 BACKGROUND & RATIONALE

4.1 Background

1 Multiple Myeloma [MM]

Multiple myeloma (MM) is a common hematologic malignancy with high disease morbidity burden in the western hemisphere. It was estimated that 70,000 new patients were diagnosed and 21,700 patients died of MM in the US in 2012.[1] MM is a clonal neoplastic proliferation of plasma cells and is considered chronic and incurable, with current novel chemo-biologic targeted agents. In the previous conventional chemotherapy era, the median overall survival was ~4-5 years for average-risk patients while this has been estimated to be much improved to >7 years in the current targeted era.[102-108] However, outcomes of high-risk or advanced MM therapy remain poor, with a median survival only ~8-14 months after therapy.[2-6]

The current standard therapy for MM is partly based on the pre-biologic targeted era when high dose therapy and autologous stem cell transplant (HDT/ASCT) was proven to improve myeloma progression-free and overall survival. This consists of 3 phases: 1) primary induction therapy 2) consolidative HDT/ASCT and 3) maintenance therapy. The immune modulating agents, thalidomide and lenalidomide, and proteasome inhibitor bortezomib, are used in the induction and maintenance, while conditioning with high-dose melphalan, a conventional chemotherapeutic agent with high anti-MM activity, remains the standard agent.[7] Despite these measures, relapse or progression during maintenance is inevitable. Retreatment with or without second HDT/ASCT is often used but of less efficacy. Few effective treatment options are available for advanced relapsed MM.

In addition, MM with certain cytogenetic abnormalities [17p-, t(4;14), t(14;16), (14:20), 13-, hypodiploidy and plasma cell leukemia] are of extremely poor prognosis, with a median survival of 8-14 months and 1-year and 2-year overall survival rates of 50% and 25% only, respectively, after HDT/ASCT [2-6]. These high risk MMs constitute ~30% of MM. Certain novel biologic agents e.g. bortezomib have been shown to overcome the resistance of these high risk MMs [8,9] but response is temporary and none is proven to be curative or to provide meaningful long-term MM control.

In the initial pioneer stage ~30 years ago, full-intensity allo-HCT was extensively explored in advanced or relapsed/refractory MM but these resulted in high early TRM, regimen related toxicities and GVHD, up to 50% in the first 6 months post transplant.[10] However, those patients who had survived subsequently enjoyed a sustained long-term MM control and likely a cure of MM. These led to the use of reduced-intensity allo-HCT in an attempt to decrease TRM in the past 15-20 years. However, the success in decreasing TRM was at the expense of increasing MM relapse, thus resulting in no improvement of overall outcomes.[11-14]

Failure of the use of allo-HCT in the advanced MM setting led to studying of its role in an upfront setting. And to improve MM control, high-dose therapy and autologous HCT was incorporated prior to reduced-intensity allo-HCT (tandem auto-allo HCTs). Several genetically randomized controlled trials (RCT) comparing tandem auto-allo HCTs versus tandem double auto-HCTs, according to the availability of matched siblings. As expected, auto-allo arms experienced increased TRM but a trend towards a better MM control after 3 years. However, there was still no definite improvement in the overall survival.[15-18]

Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 7

University of Michigan experience on allo-HCT for high-risk multiple myeloma showed a marginal improvement in outcomes, with 1-year and 2-year survival rates of 65% and 35%, respectively. Relapse rates were very high, with 1-year and 2-year progression-free survival rates of 40% and 15% only, respectively. In addition, most surviving patients suffered debilitating chronic graft- versus-host disease.[19,20]

The use of novel targeted biologic agents in primary MM therapy has improved the outcome significantly. In addition, bortezomib has been reported to overcome the poor risk karyotype t(4;14).[21] Nonetheless, recent studies of primary novel targeted biologic agents, followed by HDT/ASCT reported 1-year progression-free survival of ~50% only.[21-23]

2. Immunotherapy for Cancer

The importance of intact immune surveillance in controlling outgrowth of neoplastic transformation has been known for decades [24]. Accumulating evidence shows a correlation between tumor- infiltrating lymphocytes (TILs) in malignant tissue and favorable prognosis in various malignancies [25-29]. In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and long-term survival in many solid tumors.

The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune control. The normal function of PD-1, expressed on the cell surface of activated T-cells under healthy conditions, is to down-modulate unwanted or excessive immune responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig superfamily member related to CD28 and CTLA-4 which has been shown to negatively regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) [30; 31]. The structure of murine PD-1 has been resolved 32]. PD-1 and family members are type I transmembrane glycoproteins containing an Ig Variable-type (V-type) domain responsible for ligand binding and a cytoplasmic tail which is responsible for the binding of signaling molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM). Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 which are involved in the CD3 T-cell signaling cascade [30; 33;-35]. The mechanism by which PD-1 down modulates T-cell responses is similar to, but distinct from that of CTLA-4 as both molecules regulate an overlapping set of signaling proteins [36; 37]. PD-1 was shown to be expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer cells [38; 39]. Expression has also been shown during thymic development on CD4-CD8- (double negative) T-cells as well as subsets of macrophages and dendritic cells [40]. The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a variety of cell types, including non-hematopoietic tissues as well as in various tumors [36; 41-43]. Both ligands are type I transmembrane receptors containing both IgV- and IgC-like domains in the extracellular region and contain short cytoplasmic regions with no known signaling motifs. Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the T-cell receptor. PD-L1 is expressed at low levels on various non-hematopoietic tissues, most notably on vascular endothelium, whereas PD-L2 protein is only detectably expressed on antigen-presenting cells found in lymphoid tissue or chronic inflammatory environments. PD-L2 is thought to control immune T-cell activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T- cell function in peripheral tissues [36]. Although healthy organs express little (if any) PD-L1, a variety of cancers were demonstrated to express abundant levels of this T-cell inhibitor. PD-1

Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 8

has been suggested to regulate tumor-specific T-cell expansion in subjects with melanoma (MEL)[44]. This suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and should be considered as an attractive target for therapeutic intervention.

Similarly, dysfunction of immune surveillance of transformed cells leads to hematologic malignancies.[45,46] Chemotherapy is curative in a small proportion of patients. HDT/ASCT and allo-HCT have a curative potential in only some of these advanced refractory malignancies. In addition, allo-HCT may result in multiple debilitating or fatal complications. Thus, a safer approach of immune therapy is needed.

Passive immunotherapy includes administration of target specific monoclonal antibody e.g. anti- CD20 [rituximab] or tumor-specific effector T cells, while active immunotherapy involves the administration of tumor specific cell-based vaccines. These therapies are effective but of very short duration. The main mechanism of intolerance involves the regulatory elements e.g. immune check points [cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death-1 (PD-1) receptor/PD-1-Ligand (PD-1-L) axes) and myeloid derived suppressor cells (MDSC). Other contributing factors in the case of cell-based therapies are poor access of effector cells to activating cytokines due to presence of competitors of cytokines [cytokine sinks] and the lack of essential “space niche”.[45-48]

3. The PD-1/PD-L1 axis

PD-1 belongs to the B7 family and is a key immune check-point receptor in peripheral tissues.[28] Its ligands are the more common PD-1-L1 (B7-H1) and PD-L2 (B7-DC). It is expressed on antigen-activated T and B cells, which then become immunologically exhausted, resulting in termination of immune response after antigen activation. The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune control. The normal function of PD-1 receptors, which are expressed on the cell surface of activated T-cells under healthy conditions, are to down-regulate unwanted or excessive immune responses, including autoimmune reactions.

PD-1, which is encoded by the gene PDCD1), is an Ig superfamily member related to CD28 and CTLA-4 and has been shown to negatively regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) [49; 50]. The structure of murine PD-1 has been resolved [51]. PD-1 and family members are type I transmembrane glycoproteins containing an Ig Variable-type (V-type) domain responsible for ligand binding and a cytoplasmic tail which is responsible for the binding of signaling molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine- based switch motif (ITSM). Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 which are involved in the CD3 T-cell signaling cascade [49; 52-54]. The mechanism by which PD-1 down-regulates T-cell responses is similar to, but distinct from that of CTLA-4 as both molecules regulate an overlapping set of signaling proteins [55,56]. PD-1 is expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer cells [57,58]. Expression has also been shown during thymic development on CD4-CD8- (double negative) T-cells as well as subsets of macrophages and dendritic cells [59]. The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a variety of cell types, including non-hematopoietic tissues as well as in various tumors [55,60-62]. Both ligands are type I transmembrane receptors containing both IgV- and IgC-like domains in the extracellular region and contain short cytoplasmic regions

Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 9

with no known signaling motifs. Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the T-cell receptor. PD-L1 is expressed at low levels on various non- hematopoietic tissues, most notably on vascular endothelium, whereas PD-L2 protein is only detectably expressed on antigen-presenting cells found in lymphoid tissue or chronic inflammatory environments. PD-L2 is thought to control immune T-cell activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell function in peripheral tissues [63]. Although healthy organs express no or little PD-L1, a variety of cancers express abundant levels of this T-cell inhibitor. PD-1 has been suggested to regulate tumor-specific T-cell expansion in subjects with melanoma (MEL) [64]. This suggests that the PD-1/PD-L1 axis plays a critical role in tumor immune evasion and is an attractive target for therapeutic intervention.

For T cells, PD1 is a surface inhibitory molecule and is a receptor for its ligands, PD1-L1 and PD1-L2, which are expressed by tumor or virally infected cells.[46-48, 65] Like CTLA-4/ligand interaction, binding of PD-1 and its ligand results in inhibition of T-cell receptor (TCR) signaling and thus down-regulates T cell function (IFN-γ and IL-2 secretion) and survival/proliferation (BLC- XL). In contrast, inhibition of PD-1/PD-1-L axis by either anti-PD-1 or anti-PD1-L1 leads to enhancement of T-cell response in vitro and preclinical anti-tumor activity.[66,67]

4. Clinical Trials Targeting Cancer Immune Check Points

The largest randomized controlled trial of anti-CTLA4 to leverage anti-tumor activity in patients with advanced melanoma revealed objective response but high incidence of 46% severe grade 3/4 adverse reactions in the anti-CTLA4 alone arm.[68]

In contrast, a pilot study of a fully humanized IgG4 anti-PD-1, later known as nivolumab, as a single administration on 39 patients with advanced solid tumor, including non-small cell lung cancers, showed safety and feasibility.[69] There were no serious adverse reactions and most immune reactions were of mild severity. The plasma half-life was 12-20 days after one single infusion, with >70% sustained PD-1 receptor occupancy for >2 months. Lastly, the clinical response was sustained.

The success led to a larger phase 1 study of nivolumab on 296 patients with advanced solid tumor receiving one infusion (0.1 to 10 mg/kg) every 2 weeks for up to 2 years.[70] Nivolumab was well tolerated and MTD was not reached. The median Tmax was 1-4 hours after the start of infusion. The PK was linear, with a dose proportional increase in the Cmax and AUC calculated from day 1 to day 14 in the dose range 0.1-10 mg/kg. The median PD-1-receptor occupancy was 64-70% for the dose of 0.1-10 mg/kg every 2 weeks. The incidence of grade 3/4 adverse events was 14%, with 3 deaths from pulmonary toxicity. The cumulative response rate (CR/PR) was 20-25% and 20 of 31 responders had durable response for >1 year. Some had response for >2 years. Common adverse reactions were grade 1 or 2 and mainly immunologic skin events (rash, pruritus, urticaria, vitiligo) and diarrhea.

A more recent second phase 1 study of another anti-PD-1 (lambrolizumab; a humanized IgG4 kappa anti-PD-1 antibody) at a dose of 10 mg/kg IV every 2 or 3 weeks or 2 mg/kg IV every 3 weeks in patients with advanced melanoma for patients who had received prior treatment with the anti-CTLA-4, ipilimumab, and those who had not.[71] Steady-state serum trough concentration was 20% higher in the patients receiving 10 mg/kg every 2 weeks, compared to the same dose every 3 weeks. The serum half-life time of lambrolizumab was 2-3 weeks. Common adverse events were low-grade fatigue rash, pruritus and diarrhea. The overall response rate was 38%, with the highest response rate of 52% in the cohort receiving 10 mg/kg every 2 weeks. The

Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 10

response was sustained, with a median follow-up time of 11 months. There was no difference in the response rates of those having or not having had received anti-CTLA-4, ipilimumab.

The most recent phase 1 study of combination of anti-PD-1 nivolumab and anti-CTLA-4 ipilimumab has recently been reported.[72] The concurrent regimen for those not having had received ipilimumab consisted of IV doses of both agents in patients with advanced melanoma every 3 weeks for 4 doses followed by anti-PD-1 nivolumab alone every 3 weeks for 4 doses, followed by maintenance combined treatment every 12 weeks for up to 8 doses. The optimal doses being nivolumab at a dose of 1 mg/kg and ipilimumab at a dose of 3 mg/kg resulted in a 53% objective response rate, with all tumor reduction of 80% or more. This study revealed a more rapid and deeper degree of response with the combination of both agents targeting two different immune checkpoints.

A phase 1 study of anti-PD-L1 against the ligand PD-L1 on tumor cells was also performed on 207 patients with advanced solid tumors. [73] The dose ranged from 0.3 to 10 mg/kg every 2 weeks on a 6-week cycle basis up to 16 cycles. This agent was also very well tolerated and MTD was not reached. The grade 3/4 toxicities were only 9%. With a mean follow-up period of 12 weeks (range, 20-111 weeks), the objective response rate was 6-17% and 8 of 16 responders had a durable response (>1 year).

5. Multiple Myeloma Immune Evasion

MM is an incurable malignancy due to its intrinsic chemotherapy- and immunotherapy- refractoriness. In contrast to myeloid malignancies, allogeneic hematopoietic cell transplant and donor lymphocyte infusion have limited role in controlling or cure of MM, implicating the underlying MM-specific immune evasion. The two major possible mechanisms include[74,75]

1) Immunologically hostile microenvironment: MM cells produce multiple cytokines that promote their own survival advantage, angiogenesis and osteoclast activity leading to osteolytic lesions and resultant impaired immune response. These cytokines include TFG-β, IL-10, MUC-1, VEGF, IL-6, Fas/FasL, COX-2 and MMP. 2) Cellular immune defect: Dysfunction of T-cells, NK-cells, NKT-cells, B-cells, dendritic cells.

6. PD-1/PD-L1 axis and T cell Function in MM

A MM mouse model study showed that PD-1 expression on T cells from MM-bearing mice was up-regulated in the tumor site, compared with non-tumor sites [peripheral blood and spleen].[76] PD-1 was expressed on CD8+ and CD4+ T cells and NK cells at the tumor sites. The CD8+ T cells expressing PD-1 showed immunologically exhausting phenotype as evidenced by the impairment of IL-2, TNF-α and IFN-γ secretion and increased Tim3 expression, compared with PD-1 negative CD8+ T cells from tumor site and non-tumor sites. In addition, PD-1 was up- regulated in primary CD4+ and CD8+ T cells collected before HDT/ASCT from bone marrow and peripheral blood of MM patients. The peak of PD-1 expression occurred ~day 30 post transplant in these MM patients.[77]

Blockade of PD-1/PD-L1 axis by anti-PD-L1 against PD-L1 ligands on tumor cells enhanced efficacy of post-transplant cell based vaccine.[49] In another mouse model, it was demonstrated that anti-PD-L1 facilitated sub-ablative radiation in MM killing, which was CD8+ and CD4+ T cell dependent. With a more intensive therapy, anti-PD-L1 synergized with ablative radiation and adoptive T cell transfer.[77]

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In a similar way, blockade of this axis by anti-PD1 against PD-1 on T cells was shown to enhance T cell migration in vitro.[78] In a mouse model, anti-PD1 increased the efficacy of dendritic cell/myeloma fusion cell vaccine following HDT/ASCT.[79] The T cell response was enhanced ex vivo.[80] In another mouse model, anti-PD1 synergized with low-dose cyclophosphamide on enhancing the effect of vaccine therapy.[81]

7. PD-1/PD-L1 axis and NK cell Function in MM

Clinical observation revealed increasing NK cell dysfunction with the advancing stages of plasma cell neoplasm from MGUS to advanced stage multiple myeloma.[82] Moreover, absolute number of NK cell recovery after HDT/ASCT for patients with MM correlated with PFS and OS.[83-85]

In addition to the general immunologically hostile microenvironment – increased levels of TGF-β, IL-10, IL-6 and PGE2, which inhibits MM killing abilities by NK cells, specific mechanisms against NK function include 1) direct interference by excessive MM monoclonal immunoglobulin 2) depletion of essential cytokines by secretion of decoy soluble IL-2 receptor and expression of surface IL-15 receptors 3) modulation of NK receptor ligations including loss or down-regulation of membrane MICA, NKG2D and DNAM-1 in advanced MM, increased membrane MHC class I expression and secretion of soluble MHC class I and beta-2-microglobulin 4) down-regulation and loss-of-function mutation of membrane Fas receptors on MM cells and 5) increased expression of PD-1-ligand on MM cells.[82,86]

Pre-clinical data showed that NK cell lines were able to kill clonogenic MM cell lines in vitro and in vivo.[87] In addition, PD-1 was demonstrated to be up-regulated on primary NK cells from MM patients and MM bearing mice as a the function of MM burden.[88] In vitro data revealed that anti- PD-1 enhanced NK cell cytotoxicity against and trafficking towards PD-L1+ MM cell lines. In addition, anti-PD-1 enhanced immune complex formation between NK and MM cells. Interestingly, lenalidomide was also shown to down-regulate PD-L1 expression on MM cells and this effect was synergistic with NK cytotoxicity against PD-L1+ MM cell lines.[88]

8. Clinical Data on Leveraging NK cell versus MM effect

Two activating lymphokines, IFN-α and IL-2, were investigated in clinical trials. IFN-α was shown to have activity against MM in vitro, ex vivo and in patients. It was found to mobilize peripheral NK cells into bone marrow, the MM site.[89,90] Two large meta-analyses of these randomized controlled trials revealed a 20% response rate and prolonged PFS and OS.[91,92] Thus, IFN-α has remained a standard option for MM treatment. However, significant adverse events precluded its long-term use. Similar outcomes were seen in studies using IL-2, which increased the number of lymphokine-activated killer [LAK] cells, with modest response rate.[93-96] Unfortunately, IL-2 was associated with more unacceptable toxicities, preventing long-term use.[95-97]

Observation studies of HDT/ASCT for MM reported consistent correlation between early lymphocyte recovery and progression-free survival.[83-85,98,99] The dose of lymphocytes infused, especially the NK cell dose, predicted overall lymphocyte and NK cell recovery, which, in turn, correlated with survival.[85] Day-15 absolute lymphocyte count [ALC] >500/μL and day-30 ALC >1000/μL correlated with PFS and OS.[81,82,96,97] More specifically, day-15 absolute NK- cell count >80/μL correlated with PFS.[100] Mayo Clinic group demonstrated an augmentation of ex vivo day-14 primary NK cell cytotoxicity by IL-2 and IFN-α early post HDT/ASCT in patients with MM.[95] Lastly, Meehan et al conducted a phase 1/2 study of post-HDT/ASCT immunomodulation of NK cell function in MM patients with IL-2 therapy during lymphopenic state

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from day 0 for 4 weeks, in conjunction with GM-CSF. There was a significant increase in the + + + + + + number of CD3 T cells, CD4 Tcells, CD8 T cells and CD25 and CD8 CD56 Treg cells, compared with control.[101] Ex vivo cytotoxicity of peripheral blood mononuclear cell against MM cell lines increased significantly, compared with control.[101]

9. Homeostatic Proliferation of Lymphocytes

Active immunotherapy e.g. adoptive T cell transfer and cell based vaccines have been limited in sustained efficacy due to immune check point and other regulatory components and competition with native immune cells for space niche and essential homeostasis lymphokines.[45-48, 65]

Lympho-depletion state occurring after irradiation or chemotherapy creates a suitable condition for transferred or newly activated lymphocytes to proliferate and be activated due to depletion of competitors for space niche, cytokines (cytokine sinks) and suppressors or regulators.[102-107]

This effect is potentiated by higher intensity ablation and infusion of hematopoietic stem cells. With a higher degree of depletion of competitors or suppressor components, transferred lymphocytes proliferate and become activated more efficiently, with less intensity of antigen and co-stimulatory signals. In addition, infused hematopoietic stem cells provide more effector and precursor cells, which produce or induce other cells to secrete essential cytokines, growth factors and anti-apoptotic factors, nourishing transferred lymphocytes.[108,109] Condomines et al demonstrated a nadir of absolute lymphocyte count occurring ~day 3-8 post high-dose melphalan/HSCT in patients with MM and coinciding with the peak of serum IL-6, IL-7 and IL-15 levels.[110]

10. Previous Related Clinical Studies on Lymphoid Malignancies

A phase 2 study of a humanized anti-PD-1 monoclonal antibody, MK-3475 (Pembrolizumab), in 66 patients with diffuse large B-cell lymphoma post-HDT/ASCT.[89] MK-3475 was administered at 1.5 mg/kg every 6 weeks for 3 cycles, starting between 30-90 days post transplant. This intervention was safe and feasible. The 18-month progression free survival was 72% (95%CI; 60- 82%) overall and 70% (95% CI; 51-82%) in 24 high-risk patients with PET+ disease prior to transplant. The results were very promising, when compared with historical data. Treatment was associated with increases in circulating lymphocyte subsets including PD-L1+ lymphocytes, suggesting an on-target in vivo effect of MK-3475. [111]

A more recent phase 2 study of a combination of MK-3475 and the anti-CD20 rituximab in 32 patients with advanced rituximab-sensitive follicular lymphoma at 3 mg/kg intravenously every 4 weeks for 4 infusions, plus additional 8 optional infusions every 4 weeks for patients with stable disease or better. Rituximab was added on day 17 at 375 mg/m2 intravenously weekly for 4 weeks. The combination of MK-3475 and rituximab was well tolerated, with no autoimmune or treatment- related adverse events of grade 3 or 4. The most common adverse events of grade 1 were anaemia (14 patients) and fatigue (13 patients), and the most common adverse event of grade 2 was respiratory infection (5 patients). Of the 29 patients evaluable for activity, 19 (66%) achieved an objective response: complete responses were noted in 15 (52%) patients and partial responses in four (14%).[112]

11. Anti-PD-1: MK-3475 (Pembrolizumab)[113]

MK-3475 (previously known as SCH 900475) is a potent and highly selective humanized

Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 13

monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2 without ADCC or CDC activity.

MK-3475 strongly enhances T-lymphocyte immune responses in cultured blood cells from healthy human donors, cancer patients, and primates. In T-cell activation assays using human donor blood cells, the EC50 (concentration where 50% of the maximum effect is achieved) has been ~0.1 to 0.3 nM. In addition to interleukin-2 (IL-2), tumor necrosis factor alpha (TNFα), interferon gamma (IFNg), and levels of other cytokines were modulated by MK-3475. The antibody potentiates existing immune responses only in the presence of antigen and does not nonspecifically activate T-cells. Using an anti-murine PD-1 analog antibody, PD-1 blockade has been shown to significantly inhibit tumor growth in a variety of syngeneic murine tumor models. In these experiments in mice, anti-PD-1 therapy is synergistic with chemotherapeutic agents such as gemcitabine and 5-fluorouracil (5-FU) and combination therapy results in increased complete tumor regression rates in vivo.

Therapeutic studies in mouse models have shown that administration of antibodies blocking PD- 1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T-cells and leads ultimately to tumor rejection, either as a mono-therapy or in combination with other treatment modalities. Anti- mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated anti-tumor responses as a mono-therapy in models of squamous cell carcinoma, pancreatic carcinoma, MEL and colorectal carcinoma. Blockade of the PD-1 pathway effectively promoted CD8+ T-cell infiltration into the tumor and the presence of IFN-γ, granzyme B, and perforin, indicating that the mechanism of action involved local infiltration and activation of effector T-cell function in vivo 114-119]. Experiments have confirmed the in vivo efficacy of PD-1 blockade as a mono-therapy as well as in combination with chemotherapy in syngeneic mouse tumor models (see the Investigator’s Brochure [IB]).

Based on preclinical in vitro data, MK-3475 has high affinity and potent receptor blocking activity for PD-1. MK-3475 has an acceptable preclinical safety profile and is being advanced for clinical development as an immunotherapy for advanced malignancies.

Clinical data from PN001 is presented in the report with a visit cut-off date of 26-Jul- 2013. As of 26-Jul-2013, there have been 789 patients treated in PN001 with MK-3475 as a 30-minute IV infusion. Of these 789 patients, preliminary data are presented in this report from 479 patients. Data from 200 patients in Part B3 and 110 patients in Part F that were treated as of the cut-off data were not included in the analyses yet. Based upon this safety database consisting of patients treated up to 10 mg/kg once every two to three weeks, MK-3475 has been generally well-tolerated at doses up to 10 mg/kg every other week without DLTs. One (0.002%) patient assayed to date had samples confirmed positive for ADA, but no impact on safety has been observed. Five other clinical studies (PN002, PN006, PN010, PN011, and PN012) are ongoing however preliminary data analyses are not yet available. For these 5 studies, the number of treated patients indicated in this report is based on a visit cut-off date of 18-Oct-2013 to allow for more mature enrollment data and align with the Development Safety Update Report data cutoff date. MK-3475 PK results have been obtained from PN001 following the first dose at 1, 3 and 10 mg/kg IV of MK-3475 administered to 17 patients with solid tumors. The observed pharmacokinetic profile of MK-3475 was typical of other IgG mAbs with a half-life (t½) of approximately 2 to 3 weeks. There was no indication of dose dependency of half-life in the 3 dose groups and a dose related increase in exposure was observed from 1 to 10 mg/kg. The long half- life supports a dosing interval of every 2 or 3 weeks. Exposure obtained with sparse sampling

Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 14

after dosing melanoma and non-small cell lung cancer (NSCLC) patients at 2 and 10 mg/kg, every 2 or 3 weeks, is consistent with this profile. As of 18-Oct-2013, PN002 has randomized 497 patients with metastatic melanoma (495 patients were treated) across 3 treatment groups as follows, MK-3475 2 mg/kg Q3W, MK-3475 10 mg/kg Q3W, and chemotherapy (investigator choice of treatment) in a 1:1:1 ratio. PN006 has randomized 68 IPI-naïve patients with unresectable or metastatic melanoma across the 3 treatment groups: 10 mg/kg Q2W, 10 mg/kg Q3W, and ipilimumab in a 1:1:1 ratio. PN010 has randomized three patients with NSCLC across the 3 treatment groups: 10 mg/kg Q3W, 2 mg/kg Q3W, and docetaxel 75 mg/m2 Q3W in a 1:1:1 ratio. In PN011 10 patients have been treated. In PN012, 109 patients have been treated across the three cohorts as of 18-Oct-2013. Durable objective responses have been reported in patients with melanoma and NSCLC. Adverse events have generally been manageable and infrequently require discontinuation of MK-3475 treatment.

12. Significance

This phase 2 study is embarking on leveraging T and NK cell function after standard high-dose therapy and autologous transplant for multiple myeloma by use of anti-PD-1 to disrupt the PD- 1/PD-L-1 immune checkpoint axis. This translational concept is based on the extensive preclinical data of this axis specifically in myeloma and the positive clinical outcomes and safety profiles from recent phase I studies of this agent in patients with advanced solid tumors. Timing of treatment during post transplant lympho-penic state is expected to further enhance the effect of anti-PD-1.

Multiple myeloma is a very common hematologic malignancy in the US but remains incurable, even with novel targeted agents and high-dose therapy/autologous transplant. Immunotherapy e.g. allogeneic hematopoietic cell transplant has a curative potential but at the expense of high treatment-related mortality (graft-versus-host disease, infection and other transplant specific events). Thus, the positive outcomes of this safer strategy will definitely be a break through and has great impact on the outcomes of therapy for this common cancer.

4.2 Rationale

4.2.1 Rationale for the Study and Selected Subject Population

1. Immunotherapy is highly potent but very short-lived in clinical setting; thus meaningful clinical benefits are lacking. Reasons include: a) presence of immune checkpoints [CTLA4 and PD-1 receptor/PD-1 ligand axes]; b) presence of other suppressor elements [regulatory T cells (Treg), myeloid derived suppressor cells (MDSC)]; c) presence of competitors for essential activating cytokines for T/NK cells [Cytokine Sinks]; and d) the lack of “space niche”.

2. Patients with MM who do not respond adequately with primary therapy and those with high-risk cytogenetic features have worse treatment outcomes, compared with those who achieve a complete response status, which predicts favorable long-term outcomes. Complete response rate after primary therapy with highly effective targeted agents, followed by HDT/ASCT is disappointingly low (30% only).

3. Early lymphocyte, especially NK cells, and antigen-presenting dendritic cell recovery post- transplant is associated with decreased multiple myeloma relapse.

Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 15

4. Clinical trials using anti-Cytotoxic T-lymphocyte Antigen-4 [Anti-CTLA4] to leverage T cell function resulted in very promising anti-tumor outcomes but high rate of serious autoimmunity.

5. Preclinical studies showed increased PD-1 expression on CD8+ and CD4+ T cells and NK cells at the multiple myeloma sites and their function was impaired. Disruption of the PD-1/PD-L1 axis restored their cytotoxicity against and trafficking towards multiple myeloma. Lastly, in a mouse model, anti-PD1 increased the efficacy of dendritic cell/myeloma fusion cell vaccine following HDT/ASCT and synergized with low-dose cyclophosphamide on enhancing the effect of vaccine therapy.

6. PD-1 was expressed on primary T and NK cells from multiple myeloma patients. In addition, PD-1 was expressed on primary CD4+ and CD8+ T cells collected before and after HDT/ASCT from bone marrow and peripheral blood of MM patients. The time peak of PD-1 expression occurred ~day 30 post-transplant in these MM patients.

7. Phase 1 studies of fully humanized IgG4 anti-PD-1 in advanced cancers showed its feasibility and safety for use in human, with a sustained anti-tumor activity and a more favorable adverse reaction profile, and pharmacokinetics and -dynamics profiles.

8. Post high-dose chemotherapy lympho-depletion state is devoid of suppressor Treg or MDSC and competitors for enriching cytokines, with more available space niches.

9. In addition, transfer of hematopoietic stem cells and T cells with autologous transplant augments the above effects of lympho-depletion to T cell/immune recovery.

10. Based on the above evidence, administration of anti-PD-1 to unleash and augment T and NK cell function during lymphopenic state early post HDT/ASCT when PD-1 expression on effector cells peaks and myeloma tumor burden nadirs may result in a maximal synergy on the cytotoxicity to multiple myeloma. This may then result in the improvement of multiple myeloma relapse post transplant and overall transplant outcomes.

4.2.2 Rationale for Dose Selection/Regimen/Modification

An open-label Phase I trial (Protocol 001) was conducted to evaluate the safety and clinical activity of single agent MK-3475. The dose escalation portion of this trial evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in subjects with advanced solid tumors. All three dose levels were well tolerated and no dose-limiting toxicities were observed. This first in human study of MK-3475 showed evidence of target engagement and objective evidence of tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W). No MTD has been identified. 10.0 mg/kg Q2W, the highest dose tested in PN001, will be the dose and schedule utilized in Cohorts A, B, C and D of this protocol to test for initial tumor activity. Recent data from other clinical studies within the MK-3475 program has shown that a lower dose of MK-3475 and a less frequent schedule may be sufficient for target engagement and clinical activity.

PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic clearance, limited volume of distribution, and a long half-life (98). Pharmacodynamic data (IL-2 release assay) suggested that peripheral target engagement is durable (>21 days). This early PK and pharmacodynamic data provides scientific rationale for testing a Q2W and Q3W dosing schedule.

Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 16

A population pharmacokinetic analysis has been performed using serum concentration time data from 476 patients. Within the resulting population PK model, clearance and volume parameters of MK-3475 were found to be dependent on body weight. The relationship between clearance and body weight, with an allometric exponent of 0.59, is within the range observed for other antibodies and would support both body weight normalized dosing or a fixed dose across all body weights. MK-3475 has been found to have a wide therapeutic range based on the melanoma indication. The differences in exposure for a 200 mg fixed dose regimen relative to a 2 mg/kg Q3W body weight based regimen are anticipated to remain well within the established exposure margins of 0.5 – 5.0 for MK-3475 in the melanoma indication. The exposure margins are based on the notion of similar efficacy and safety in melanoma at 10 mg/kg Q3W vs. the proposed dose regimen of 2 mg/kg Q3W (i.e. 5-fold higher dose and exposure). The population PK evaluation revealed that there was no significant impact of tumor burden on exposure. In addition, exposure was similar between the NSCLC and melanoma indications. Therefore, there are no anticipated changes in exposure between different indication settings.

The dose regimen of 200 mg Q3W of MK-3475 is planned for all urothelial cancer trials. Available PK results in subjects with melanoma, non-small cell lung cancer (NSCLC), and other solid tumor types support a lack of meaningful difference in PK exposures obtained at a given dose among tumor types. An open-label Phase 1 trial (PN001) in melanoma subjects is being conducted to evaluate the safety and clinical activity of single agent MK-3475. The dose escalation portion of this trial evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in subjects with advanced solid tumors. All three dose levels were well tolerated and no dose-limiting toxicities were observed. This first in human study of MK-3475 showed evidence of target engagement and objective evidence of tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W). No maximum tolerated dose (MTD) has been identified.

In KEYNOTE-001, two randomized cohort evaluations of melanoma subjects receiving MK-3475 at a dose of 2 mg/kg versus 10 mg/kg Q3W have been completed. The clinical efficacy and safety data demonstrate a lack of clinically important differences in efficacy response or safety profile at these doses. For example, in Cohort B2, advanced melanoma subjects who had received prior ipilimumab therapy were randomized to receive MK-3475 at 2 mg/kg versus 10 mg/kg Q3W. The overall response rate (ORR) was 26% (21/81) in the 2mg/kg group and 26% (25/79) in the 10 mg/kg group (full analysis set (FAS)). The proportion of subjects with drug-related adverse events (AEs), grade 3-5 drug-related AEs, serious drug-related AEs, death or discontinuation due to an AE was comparable between groups or lower in the 10 mg/kg group.

Available pharmacokinetic results in subjects with melanoma, NSCLC, and other solid tumor types support a lack of meaningful difference in pharmacokinetic exposures obtained at a given dose among tumor types. Population PK analysis has been performed and has confirmed the expectation that intrinsic factors do not affect exposure to MK-3475 to a clinically meaningful extent. Taken together, these data support the use of lower doses (with similar exposure to 2 mg/kg Q3W) in all solid tumor indications. 2 mg/kg Q3W is being evaluated in NSCLC in PN001, Cohort F30 and PN010, and 200 mg Q3W is being evaluated in head and neck cancer in PN012, which are expected to provide additional data supporting the dose selection.

Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 17

covariates on exposure, has been developed using available data from 476 subjects from PN001. The distribution of exposures from the 200 mg fixed dose are predicted to considerably overlap those obtained with the 2 mg/kg dose, with some tendency for individual values to range slightly higher with the 200 mg fixed dose. The slight increase in PK variability predicted for the fixed dose relative to weight-based dosing is not expected to be clinically important given that the range of individual exposures is well contained within the range of exposures shown in the melanoma studies of 2 and 10 mg/kg to provide similar efficacy and safety. The population PK evaluation revealed that there was no significant impact of tumor burden on exposure. In addition, exposure was similar between the NSCLC and melanoma indications. Therefore, there are no anticipated changes in exposure between different tumor types and indication settings.

Based on the PK/PD data, and the time peak of PD-1 expression on primary T-cells at day 30 post-transplant in MM patients,[40] we will study anti-PD-1 at a fixed dose of 200 mg MK-3475 intravenously every 3 weeks (+/-4 days), starting on day +14 or later after an engraftment until ~day 182 post-transplant for a total of 9 doses. [See Schema]

4.2.3 Rationale for Endpoints

See Section 5.10 and Appendix 13.3 for the definition of Endpoints.

4.2.3.1 Efficacy Endpoints

We expect that the addition of anti-PD1 during lymphopenic state after high dose therapy and autologous transplant will augment immune reaction against multiple myeloma and increase complete response (CR) conversion rate at day 180.

Primary Efficacy Endpoint: CR rate at day 180

Secondary Efficacy Endpoints

- CR rate at day 100 - Flow based minimal residual disease (MRD) rate at day 100 and day 180 - Progression-free survival at 2 years - Overall survival at 2 years - Compliance with treatment: o Median Number of doses administered o Dose de-escalation requirements

4.2.3.2 Safety Endpoints

- Regimen-related toxicities (RRT) according to CTCAE v4 - Engraftment - Treatment-related mortality (TRM) - Late adverse reactions especially autoimmune disorders

4.2.3.3 Biomarker Research

1) Measurement of immune cell phenotypes in autologous graft tissue pre- transplant

Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 18

2) Quantification of immune recovery: Quantification of activated and effector CD4+ and CD8+ cells, NK cells, and regulatory T and B cells. 3) Functional T cell subtypes and cytokine profiles: Intracellular IFN-α, IFN-γ, cytokine

release spectrum, TH subset transcription factor profiling 4) NK cell cytotoxicity: Intracellular granzyme B, tumor cell death 5) PD-1-ligand expression on MM cells pre-transplant

5.0 METHODOLOGY

5.1 Entry Criteria

5.1.1 Diagnosis/Condition for Entry into the Trial

1. Subjects with multiple myeloma (MM) of any stage and of any cytogenetic risk per International Multiple Myeloma Working Group Criteria (Appendix 13.2).

Pathology review by Pathology Department of each institution is mandatory.

2. Has no progressive disease (PD; Appendix 13.3) after initial primary therapy

AND

Has either of the following suboptimal response with primary therapy

2.1 Very good partial response (VGPR) or less (Appendix 13.3) after at least 2 cycles of a triple regimen:

An *IMiDs, a proteasome inhibitor and a systemic steroid OR

A conventional chemotherapy, a proteasome inhibitor and a systemic steroid OR

An equivalent triple regimen at the investigator discretion

*IMiDs consists of thalidomide, lenalidomide, pomalidomide and other related –lidomides.

2.2 VGPR or less after at least 4 cycles of a double regimen:

An IMiDs and a systemic steroid OR

A proteasome inhibitor and a systemic steroid OR

An equivalent double regimen at the investigator discretion

5.1.2 Subject Inclusion Criteria

In order to be eligible for participation in this study, the subject must:

3. Be ≥ 18 years and ≤75 of age on day of signing informed consent.

Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 19

4. Had measurable disease of MM at diagnosis, defined as:

o A monoclonal immunoglobulin spike on serum electrophoresis of at least 0.5 g/dL and/or o Urine monoclonal protein levels of at least 200 mg/24 hours

o For subjects without measurable serum or urine M-protein levels, an abnormal free light chain ratio (normal value: 0.26-1.65) with involved FLC level ≥10 mg/dL (≥100 mg/L).

“Measurable disease” is NOT required at the time of enrollment. See “required MM status at enrollment” in 5.1.1 #2. Final determination of measurable disease requirement is at PI’s discretion.

5. Has no other hematopoietic stem cell transplant of any type prior to the current planned autologous hematopoietic cell transplant.

6. Has a performance status of 0 or 1 on the ECOG Performance Scale. (≥70% Karnofsky Performance Score) (Appendix 13.1).

7. Demonstrate adequate organ function per institutional guidelines for high-dose melphalan and autologous transplant at the time of enrollment. See separate laboratory criteria to initiate MK-3475 at day +14 post transplant (Table 1) which are not required at enrollment.

8. Has had a successful peripheral blood stem cell collection with G-CSF (Filgrastim) +/- Plerixafor (Mozobil) only. The target cell dose is ≥2.0 x106 CD34+ cells/kg.

9. Be willing and able to provide written informed consent/assent for the study.

10. Female subject of childbearing potential should have a negative urine or serum pregnancy per institutional guidelines for high-dose melphalan and autologous transplant. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.

11. Female subjects of childbearing potential must be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study starting with the first dose of MK-3475 through 120 days after the last dose of MK-3475 (Section 5.5.4). Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for >2 year (Section 5.5.4).

12. Male subjects must agree to use an adequate method of contraception starting with the first dose of MK-3475 through 120 days after the last dose of MK-3475 (Section 5.5.4).

13. Subject is able to swallow capsules and is able to take or tolerate oral medications on a continuous basis. 5.1.3 Subject Exclusion Criteria

Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 20

The subject must be excluded from participating in the trial if the subject:

1. Has any type of amyloidosis, hyperviscosity, plasma cell leukemia, POEMS syndrome, Waldenström's macroglobulinemia, non-secretory multiple myeloma or IgM myeloma. 2. Has known clinically active CNS involvement OR history of resolved CNS involvement by multiple myeloma. 3. Has an active autoimmune disease or a documented history of autoimmune disease, or an autoimmune syndrome that requires systemic steroids or immunosuppressive agents. Note: Subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid injections would NOT be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjorgen’s syndrome will NOT be excluded from the trial.

4. Has a history of non-infectious pneumonitis that required steroids or current pneumonitis. 5. Has evidence of interstitial lung disease. 6. Has a diagnosis of immunosuppressive disorder OR is on any other form of immunosuppressive therapy within 7 days prior to transplant admission. 7. Is currently participating in or has participated in any study of an investigational agent or using an investigational device within 4 weeks of transplant admission. 8. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways). 9. Has had prior monoclonal antibody, chemotherapy (including dexamethasone for MM treatment), targeted small molecule therapy, or radiation therapy within 2 weeks prior to transplant admission (or ~4 weeks prior to the first dose of MK-3475).

OR Has not recovered (i.e. ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent more than 2 weeks prior to transplant admission or more than 4 weeks prior to the first dose of MK-3475.

Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.

Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to transplant admission.

Note: Toxicity that has not recovered to ≤ Grade 1 is allowed if it meets the requirements per institutional guidelines for high-dose melphalan and autologous transplant.

10. Has been free of additional malignancy for at least 5 years. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy.

Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 21

11. Has an active infection requiring systemic therapy or history of repeated infections. 12. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study. 13. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the pre-screening or screening visit through 120 days after the last dose of MK-3475 (Section 5.5.4). 14. Has a known Human Immunodeficiency Virus (HIV), Hepatitis B (HBV), or Hepatitis C (HCV) infection. 15. Has a clinically significant coagulopathy per investigator’s assessment. 16. Has known symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia. 17. Has received any type of hematopoietic cell transplant except for the current planned high dose melphalan and autologous stem cell transplant.

18. Has received a live vaccine within 30 days prior to transplant admission. 19. Is or has an immediate family member (spouse or children) who is investigational site or sponsor staff directly involved with this study, unless prospective IRB approval (by chair or designee) is given allowing exception to this criterion for a specific subject. 5.2 Inclusion Criteria to initiate on the first dose of MK-3475 on day 14

The subject must demonstrate adequate organ function as defined in Table 1 prior to receiving the first dose of MK-3475 on day+14 (+/-4) post transplant. All labs should be performed within 3 days of MK-3475 treatment initiation.

Table 1: Required Organ Function Laboratory Values Prior to the first MK-3475 Initiation only

System Laboratory Value Hematological Absolute neutrophil count (ANC) ≥1,000 /µL Platelets ≥20,000 / µL Hemoglobin ≥8 g/dL Renal ≤1.5 X upper limit of Serum creatinine normal (ULN) OR OR

Measured or calculated1 creatinine clearance ≥ 60 mL/min for subject

with creatinine levels > (GFR can also be used in place of creatinine or CrCl) 1.5 X institutional ULN Hepatic Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for

subjects with total

Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 22

bilirubin levels > 1.5 X ULN AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN Coagulation International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range Activated Partial Thromboplastin Time (aPTT) of intended use of anticoagulants

≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants 1 Creatinine clearance should be calculated per institutional standard.

Note: These criteria in Table 1 are not required or applicable to 8 subsequent doses of MK-3475. Refer to 5.3.4.7 (Event of Clinical Interest (ECI) and immune-related Adverse Event (irAE)) and 5.3.4.8 (Dose Modification) for management of 8 subsequent doses.

Subject Screening and Registration Procedure

Subject registration for this study will be centrally managed by the Oncology Clinical Trials Support Unit (O-CTSU) of The University of Michigan Comprehensive Cancer Center as described below:

A potential study subject who has been screened for the study and who has signed the Informed Consent document will be initially documented by the participating site on the Screening and Enrollment Log provided by the O-CTSU.

It is the responsibility of the local site investigator to determine subject eligibility prior to submitting subject registration request to the O-CTSU. After subject eligibility has been determined, a copy of the completed Eligibility Worksheet together with all the pertinent de-identified source documents will be submitted by the requesting site to the O-CTSU, by email to CTSU-Oncology- [email protected].

A Multi-Site Coordinator (MSC) of the CTSU, who acts as the registrar, will review the submitted documents and process the registration. Sites should inform the Multi-Site Coordinator of a potential registration by 5 p.m. on the day prior to registration. Same day registrations cannot be guaranteed.

An email will be sent by the registrar to the requesting site registrar to confirm patient registration and to provide the study identification number that has been assigned to the patient. In addition,

Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 23

a copy of the completed Section of the Eligibility Worksheet signed and dated by the registrar, will be returned to the requesting site registrar.

Subjects found to be ineligible for participation after being consented will be considered screen failures, and documented as such in the Screening and Enrollment Log. These subjects will not have study identification number assigned to them, and will not receive study treatment.

Pre-study Documentation Requirements

Informed consent, eligibility checklist and registration forms shall be obtained before subjects can receive the first study treatment of MK-3475 (pembrolizumab).

Informed consent, eligibility checklist and registration forms should be obtained before “transplantation”. Failure to complete the registration before transplantation may be allowed at the discretion of the PI and will not be considered a protocol deviation or violation.

Of note, conditioning chemotherapy (melphalan), autologous hematopoietic cell transplantation and lenalidomide maintenance therapy are standard treatments (see 5.3).

5.3 TREATMENTS

5.3.1 Standard Multiple Myeloma Treatment

5.3.1.1 High-dose Melphalan and Autologous Stem Cell Transplantation

1. High-dose melphalan 140-200 mg/m2 (<200 mg/m2 for subjects aged >70 years)

2. The procedure protocol of high-dose melphalan and autologous stem cell transplant follows Institutional Guidelines. The target cell dose is ≥2.0 x106 CD34+ cells/kg.

3. Use of filgrastim (Neupogen®) to facilitate engraftment is allowed per Institutional Guidelines

5.3.1.2 Maintenance Treatment

Lenalidomide 5-15 mg/day to start on day 45-90 post-transplant per standard multiple myeloma management as tolerated until multiple myeloma progression.

Venous thromboembolism prevention and contraception required during lenalidomide maintenance treatment will follow standard of care or Institution Guidelines. Of note, warfarin is not allowed (see Section 5.4.2).

**Failure to follow the standard multiple myeloma treatment procedures due to appropriate medical indications may not be considered a protocol deviation or violation at the PI’s discretion.**

5.3.2 Study Treatment with MK-3475 (Pembrolizumab)

Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 24

A fixed MK-3475 dose of 200 mg/day will be administered as a 30-minute intravenous (IV) infusion every 3 weeks, starting ~day +14 post-transplant (Schema). Dose days are 4 days flexible (+/- 4 days).

Sites should make every effort to target infusion timing to be as close to 30 minutes as possible. However, given the variability of infusion pumps from site to site, a window of -5 minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min).

Treatment Schema

Table 2: Study Treatment Drug Dose/Potency Dose Route of Regimen/Treatment Use Frequency Administration Period MK-3475 200 mg Every 3 IV infusion Starting day +14 for Experimental (Pembrolizumab) weeks a total of 9 doses (+/- 4 days)

The MK-3475 dosing interval may be increased due to toxicity as described in Section 5.3.4.8 (Table 4 and 5)

Premedication per institutional guidelines for monoclonal antibodies (e.g. acetaminophen and antihistamine) is allowed. Steroid premedication is not indicated and should be avoided.

5.3.3 Standard Transplantation Drugs

1. Melphalan [Evomela, Alkeran] Formulation: Melphalan (L-phenylanine mustard) is a bifunctional alkylating agent. It forms covalent linkages with susceptible cellular proteins. It induces formation of DNA interstrand and DNA protein cross-links. Alkeran: IV administration of melphalan revealed rapid elimination from plasma with terminal half-life of 1.8 hours. 13% is excreted in the urine. It is rapidly distributed in total body water and eliminated in a biphasic manner. IP administration of 20-30 mg/M2 revealed a peak concentration in the peritoneal cavity of 6.4 ± 2.4 µg/ml and half-life of 85 ± 30 minutes. The peak plasma concentration was 1.22 µg/ml, and half-life was 86 ± 31 minutes. Evomela: IV administration has a comparable PK profile to conventional IV melphalan (Alkeran).

Availability: Alkeran: The drug is available as an injectable kit. This kit contains an ampule of 100 mg (equivalent) melphalan, a 1 ml ampule of acid- alcohol diluent (containing 0.047 ml 37%

Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 25

HCl, q.s. to 1 ml with alcohol) and a 9 ml ampule of final diluent containing dipotassium phosphate, 108 mg propylene glycol 5.4 ml sterile water for injection q.s. 9.0 ml. Evomela: The drug is available as a lyophilized powder in a single-dose vial for intravenous use. Each vial contains 50 mg melphalan free base equivalent to 56 mg melphalan hydrochloride and 2700 mg Betatex Sulfobutyl Ether Sodium. The Alkeran kits and Evomela vials should be stored at room temperature and projected from light.

Administration: Alkeran: The 100 mg injectable formulation is put into solution initially with the addition of 1 m acid-alcohol diluent. When dissolution is complete, the 9 ml final diluent is added. This final solution has a pH of > 7 and should be used promptly. According to the manufacturer (8.5% hydrolysis 24 hours after mixing) a further dilution in D5W is also reportedly stable for 24 hours. Evomela: Each 50 mg vial is reconstituted with 8.6 mL of normal saline solution (0.9% Sodium Chloride Injection, USP) to make a 50 mg/10 mL (5 mg/mL) nominal concentration of melphalan. The reconstituted Evomela drug product is stable for: 24 hours at refrigerated temperature (5oC) without any precipitation due to the high solubility, and for 1 hour at room temperature. Add the required volume of Evomela to the appropriate volume of 0.9% Sodium Chloride Injection, USP to a final concentration of 0.45 mg/mL. The Evomela admixture solution is stable for 4 hours at room temperature in addition to the 1 hour following reconstitution.

Potential and Expected Toxicities: Human Toxicology: Melphalan's major systemic toxicity is bone marrow depression with secondary anemia, leukopenia and thrombocytopenia, usually occurring within three to five weeks of the onset of therapy and lasting four to eight weeks. These effects are exacerbated by prior chemotherapy or radiotherapy. Other adverse reactions include nausea, vomiting, diarrhea, stomatitis, esophagitis, colitis, increases in liver function and kidney function tests, renal/bladder necrosis, pulmonary fibrosis, respiratory distress, peripheral neuropathy, paresthesia, alopecia, fever and hypersensitivity including edema, rash and anaphylaxis. At high doses, supraventricular arrhythmias, including atrial fibrillation, may occur. The occurrence of acute leukemia has been reported rarely in patients treated with anthracycline/alkylator combination chemotherapy.

2. FILGRASTIM (r-metHuG-CSF, NEUPOGEN®) Formulation: Filgrastim, (recombinant human granulocyte-colony stimulating factor, r-metHuG- CSF), is a protein produced by E. coli into which has been inserted the human granulocyte colony- stimulating factor gene. Filgrastim differs from the natural protein in that the N-terminal amino acid is a methionine and it is not o- glycosylated. G-CSF functions as a hematopoietic growth hormone; it increases the proliferation, differentiation, maturation and release of precursor cells into mature blood cells of the neutrophil lineage. G-CSF has demonstrated in vitro effects on mature neutrophils, including an increased expression of chemotactic receptors, enhanced phagocytosis and intracellular killing of certain organisms, as well as enhanced killing of target cells that are bound by antibodies. Approximately 6,400 patients in U.S. and international based trials have participated in clinical trials of filgrastim to date, and the worldwide commercial populations receiving filgrastim totaled approximately 190,000. The drug has been found to be well tolerated at dosages up to 69 µg/kg/day given IV or SC, with no toxic effects attributable to filgrastim. A maximum tolerated dose has not yet been determined.

Availability: Recombinant G-CSF, filgrastim, NEUPOGEN®, is supplied as a clear, colorless preservative-free liquid for parenteral administration. Single use vials contain filgrastim 300 µg/ml in a preservative-free solution with 0.59 mg/ml acetate, 50 mg/ml sorbitol, 0.004% Tween® 80, 0.035 mg/ml sodium, and water for injection, USP, pH 4.0 to make 1 ml filgrastim Neupogen® is

Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 26

commercially available in 2 vial sizes: 300 µcg/1 ml and 480 µg/1.6 ml. Dilution: If required, filgrastim may be diluted in 5% dextrose. Filgrastim diluted to concentrations between 5 and 15 µg/ml should be protected from adsorption to plastic materials by addition of albumin (Human) to a final concentration of 2 mg/ml. When diluted in 5% dextrose or 5% dextrose plus albumin (Human), filgrastim is compatible with glass bottles, PVC and polyolefin IV bags, and polypropylene syringes. Dilution of filgrastim to a final concentration of less than 5 µg/ml is not recommended at any time. Do not dilute with saline at any time; product may precipitate. Storage and Stability: Filgrastim should be stored in the refrigerator at 2 - 8°C (36 - 46°F). Avoid shaking. Prior to injection, filgrastim may be allowed to reach room temperature for a maximum of 24 hours Any vial left at room temperature for greater than 24 hours should be discarded. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit; if particulates or discoloration are observed, the container should not be used.

Administration: Filgrastim is administered as a single daily injection by SC bolus injection, by short IV infusion (15 - 30 minutes), or by continuous SC or continuous IV infusion.

Potential and Expected Toxicities: The most frequently reported adverse effect was medullary bone pain, occurring in 20 - 25% of patients in Phase II and III trials. When bone pain was reported it often preceded a rise in the circulating neutrophil count; it occurred more frequently in patients treated with 20 - 100 µg/kg/day of intravenously administered filgrastim and less often in lower subcutaneous doses. The pain was generally mild to moderate in severity, and usually controlled with non-narcotic analgesics such as acetaminophen. Other side effects include transient but reversible increases of alkaline phosphatase, lactate dehydrogenase and uric acid levels. These occurred in 27-58% of patients, without clinical sequelae observed. Elevations of leukocyte alkaline phosphatase levels have also been noted but the significance is not yet known. Less frequently reported adverse events related to filgrastim administration include subclinical splenomegaly, exacerbation of pre-existing skin rashes, alopecia, and thrombocytopenia, and cutaneous vasculitis. Rarely, allergic-type reactions have occurred. Since the commercial introduction of filgrastim there have been reports (< 1 in 4,000 patients) of symptoms suggestive of an allergic-type reaction, but in which an immune component has not been demonstrated. These have generally been characterized by systemic symptoms involving at least two body systems, most often skin (rash, urticaria, edema), respiratory (wheezing, dypsnea), and cardiovascular (hypotension, tachycardia). Some reactions occurred on initial exposure. Reactions tended to occur within the first thirty minutes after administration and appeared to occur more frequently in those patients who received filgrastim intravenously. Rapid resolution of symptoms occurred in most cases after administration of standard supportive care, and symptoms recurred in more than half the patients when rechallenged.

3. LENALIDOMIDE (REVLIMID®) Formulation: A thalidomide analogue, is an immunomodulatory agent with anti-angiogenic properties. The chemical name is 3-(4-amino-1-oxo 1,3-dihydro -2H-isoindol-2-yl) piperidine-2,6- dione and the gram molecular weight is 259.3. The mechanism of action of lenalidomide remains to be fully characterized. Lenalidomide possesses immunomodulatory and antiangiogenic properties. Lenalidomide inhibited the secretion of proinflammatory cytokines and increased the secretion of anti-inflammatory cytokines from peripheral blood mononuclear cells. Lenalidomide inhibited the expression of cyclooxygenase-2 (COX-2) but not COX-1 in vitro. Lenalidomide, in healthy volunteers, is rapidly absorbed following oral administration with maximum plasma concentrations occurring between 0.625 and 1.5 hours post-dose. Co administration with food does not alter the extent of absorption (AUC) but does reduce the maximal plasma concentration

Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 27

(Cmax) by 36%. The pharmacokinetic disposition of lenalidomide is linear. Cmax and AUC increase proportionately with increases in dose. Multiple dosing at the recommended dose- regimen does not result in drug accumulation. In multiple myeloma patients maximum plasma concentrations occurred between 0.5 and 4.0 hours post-dose both on Days 1 and 28. AUC and Cmax values increase proportionally with dose following single and multiple doses. Exposure (AUC) in multiple myeloma patients is 57% higher than in healthy male volunteers.

Availability: Lenalidomide (REVLIMID®) is available in 5, 10, 15 and 25 mg capsules for oral administration. Each capsule contains lenalidomide as the active ingredient and the following inactive ingredients: lactose anhydrous, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. The 5 mg capsule shell contains gelatin, titanium dioxide and black ink. The 10 mg capsule shell contains gelatin, FD&C blue #2, yellow iron oxide, titanium dioxide and black ink. Lenalidomide is an off-white to pale-yellow solid powder. It is soluble in organic solvent/water mixtures, and buffered aqueous solvents. Lenalidomide is more soluble in organic solvents and low pH solutions. Solubility was significantly lower in less acidic buffers, ranging from about 0.4 to 0.5 mg/ml. Lenalidomide has an asymmetric carbon atom and can exist as the optically active forms S(-) and R(+), and is produced as a racemic mixture with a net optical rotation of zero.

Administration: Lenalidomide (REVLIMID®) is administered as an oral route, preferably at the same time.

Potential and Expected Toxicities: Hematologic: anemia, neutropenia, leucopenia, lymphopenia and thrombocytopenia; thromboembolic events (deep vein thrombosis and pulmonary embolism). Neurologic: Somnolence, dizziness, headache, confusion, tremor, loss of co-ordination, asthenia, paresthesia, numbness, and leukoencephalopathy (radiographic findings). Gastrointestinal: Constipation, dehydration, dry mouth, diarrhea, dyspepsia, nausea, vomiting and stomatitis. Constitutional: Weakness, insomnia, rigors, chills, sweating, weight loss and fever. Reproductive: teratogenicity and miscarriage. Musculoskeletal: arthralgia, back/neck pain, joint pain, muscle cramp and weakness. Cardiac: hypotension. Dermatologic: rash, dry skin, itching. Endocrine: hypothyroidism. Infection. Pulmonary: cough, dyspnea. Metabolic: hypokalemia, liver damage. Renal: increased creatinine, renal failure.

Note: Pregnancy reporting: Due to its structural similarities to thalidomide, a known human teratogen, lenalidomide is contraindicated in pregnant women and women capable of becoming pregnant. When there is no alternative, females of childbearing potential may be treated with lenalidomide provided adequate precautions are taken to avoid pregnancy. Females must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, including at least one highly effective method (e.g., IUD, hormonal contraception, tubal ligation, or partner’s vasectomy) and one additional effective method (e.g., latex condom, diaphragm, or cervical cap), beginning 4 weeks prior to initiating treatment with REVLIMID® (lenalidomide), during therapy with REVLIMID® (lenalidomide), during therapy delay, and continuing for 4 weeks following discontinuation of REVLIMID® (lenalidomide) therapy. If hormonal or IUD contraception is medically contraindicated, two other effective or highly effective methods may be used.

Note: Deep Venous Thrombosis and Pulmonary Embolism: lenalidomide has demonstrated a significantly increased risk of DVT and PE in patients with multiple myeloma who were treated with REVLIMID® (lenalidomide) combination therapy. Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Patients should be instructed to

Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 28

seek medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling.

5.3.4 Study Drug: MK-3475 (Pembrolizumab) 5.3.4.1 Description MK-3475 is a potent humanized IgG4 monoclonal antibody with high specificity of binding to the PD-1receptor, thus inhibiting its interaction with PD-L1 and PD-L2. Based on preclinical in vitro data, MK-3475 has high affinity and potent receptor blocking activity for PD-1. MK-3475 has an acceptable preclinical safety profile.

MK-3475 is a humanized anti-PD-1 mAb of the IgG4/kappa isotype with a stabilizing S228P sequence alteration in the fragment crystallizable (Fc) region. MK-3475 binds to human PD-1 and blocks the interaction between PD-1 and its ligands. The theoretical molecular weight of the polypeptide is 146,288 Da and its theoretical pI is 7.5. The parental murine anti-human PD-1 antibody (hPD-1.09A) was produced by immunizing mice with hPD-1 DNA. The MK-3475 antibody was generated by humanization of the parental antibody by the Medical Research Council (Cambridge, UK) using complementarily-determining region (CDR) grafting technology (U.S. Patent No. 5,225,539). The gene segments encoding the variable heavy and light chains of MK- 3475, as well as human IgG4, were codon-optimized, synthesized, and ligated into a vector.

A single expression plasmid, pAPD11V1-GA was constructed for the expression of both the heavy and light antibody chains of MK-3475. The nucleotide sequences encoding the heavy and light chains, along with their respective promoters and poly A signal sequences have been confirmed by DNA sequence analysis. The pAPD11V1-GAexpression vector was subsequently used to transfect CHO-DXB-11 cells for the development of the MK-3475-producing cell line.

5.3.4.2 Formulation

MK-3475 Solution will be used. Refer to the Investigator Brochure (IB).

5.3.4.3 Storage MK-3475 Solution is stored under refrigerated conditions (2°C - 8°C). Refer to the IB.

5.3.4.4 Administration MK-3475 is administered as a 30-minute IV infusion. Refer to the IB.

5.3.4.5 Dose Selection

Dose Selection Rationale The dose regimen of 200 mg Q3W of MK-3475 is planned for all urothelial cancer trials. Available PK results in subjects with melanoma, NSCLC, and other solid tumor types support a lack of meaningful difference in PK exposures obtained at a given dose among tumor types. An open- label Phase 1 trial (PN001) in melanoma subjects is being conducted to evaluate the safety and clinical activity of single agent MK-3475. The dose escalation portion of this trial evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in subjects with advanced solid tumors. All three dose levels were well tolerated and no dose-limiting toxicities were observed. This first in human study of MK-3475 showed evidence of target engagement and objective evidence of tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W). No maximum tolerated dose (MTD) has been identified.

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In KEYNOTE-001, two randomized cohort evaluations of melanoma subjects receiving pembrolizumab at a dose of 2 mg/kg versus 10 mg/kg Q3W have been completed. The clinical efficacy and safety data demonstrate a lack of clinically important differences in efficacy response or safety profile at these doses. For example, in Cohort B2, advanced melanoma subjects who had received prior ipilimumab therapy were randomized to receive pembrolizumab at 2 mg/kg versus 10 mg/kg Q3W. The overall response rate (ORR) was 26% (21/81) in the 2mg/kg group and 26% (25/79) in the 10 mg/kg group (full analysis set (FAS)). The proportion of subjects with drug-related adverse events (AEs), grade 3-5 drug-related AEs, serious drug-related

SAEs, death or discontinuation due to an AE was comparable between groups or lower in the 10 mg/kg group.

Selection of 200 mg as the appropriate dose for a switch to fixed dosing is based on simulation results indicating that 200 mg will provide exposures that are reasonably consistent with those obtained with 2 mg/kg dose and importantly will maintain individual patient exposures within the exposure range established in melanoma as associated with maximal clinical response. A population PK model, which characterized the influence of body weight and other patient covariates on exposure, has been developed using available data from 476 subjects from PN001. The distribution of exposures from the 200 mg fixed dose are predicted to considerably overlap those obtained with the 2 mg/kg dose, with some tendency for individual values to range slightly higher with the 200 mg fixed dose. The slight increase in PK variability predicted for the fixed dose relative to weight-based dosing is not expected to be clinically important given that the range of individual exposures is well contained within the range of exposures shown in the melanoma studies of 2 and 10 mg/kg to provide similar efficacy and safety. The population PK evaluation revealed that there was no significant impact of tumor burden on exposure. In addition, exposure was similar between the NSCLC and melanoma indications. Therefore, there are no anticipated changes in exposure between different tumor types and indication settings.

The treatment to be used in this study is outlined below in Table 2.

Table 2: Study Treatment

Drug Dose/Potency Dose Route of Regimen/Treatment Use Frequency Administration Period MK-3475 200 mg Every 3 IV infusion Starting day +14 for Experimental (Pembrolizumab) weeks (+/- a total of 9 doses 4 days) The MK-3475 dosing interval may be increased due to toxicity as described in Section 5.3.4.8 (Table 4 and 5)

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A fixed dose of 200 mg/day will be administered as a 30 minute IV infusion every 3 weeks. Sites should make every effort to target infusion timing to be as close to 30 minutes as possible. However, given the variability of infusion pumps from site to site, a window of -5 minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min).

Premedication per institutional guidelines for monoclonal antibodies (e.g. acetaminophen and antihistamine) is allowed. Steroid premedication is not indicated and should be avoided.

5.3.4.6 Timing of Dose Administration MK-3475 will be started on “day +14 post-transplant” AND “after all assessments prior to the first dose of MK-3475” have been completed as detailed in Table 1 and the Study Flow Chart (Section 6.0).

The criteria to initiate the first dose of MK-3475 on day 14 in Table 1 are NOT required or applicable to 8 subsequent doses of MK-3475. Refer to the Study Flow Chart (Section 6.0), Section 5.3.4.7 (Event of Clinical Interest (ECI) and immune-related Adverse Event (irAE)) and Section 5.3.4.8 (Dose Modification) for required assessments prior to and managements of 8 subsequent doses of MK-3475, respectively.

MK-3475 may be administered up to +/- 4 days of each dose of MK-3475 due to clinical and administrative reasons.

MK-3475 will be administered on an outpatient basis, but may be administered during transplant admission as appropriate.

5.3.4.7 Event of Clinical Interest (ECI) and immune-related Adverse Event (irAE) An ECI is defined as an immune-related adverse event (irAE) that is considered MK-3475 related, after other causes are excluded.

An irAE is defined as a clinically significant AE of any organ system that is associated with MK- 3475 exposure and is consistent with an immune-related mechanism. irAEs were reported in 21.4% of melanoma patients; most of these events (15.8%) were considered drug-related by the investigator. The most commonly reported irAEs across the dose schedules are rash (3.2%), pruritus (2.9%), vitiligo (2.9%), hypothyroidism (2.7%), arthralgia (2.2%), diarrhea (2.2%), and pneumonitis (1.9%). The organ most frequently affected by irAEs with MK-3475 is the skin. Less frequently affected tissues include thyroid gland, colon, lung, kidney, and liver. Severe but rare irAEs include Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) and immune-mediated myocarditis.

ECI/irAEs can be categorized according to organ systems or syndromes (see the Manual “Pembrolizumab Program (MK-3475): Event of Clinical Interest Guidance Document”).

ECI/irAEs must be reported to Merck according to the Manual “Pembrolizumab Program (MK- 3475): Event of Clinical Interest Guidance Document” within a specified time period (e.g. within 24 hours according to the Document Version most updated. See Section 7.2.3.2 for reporting procedure.

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5.3.4.8 Dose Modification

For immune-related AEs, including immune-related hematologic AEs (e.g. autoimmune hemolytic anemia, immune thrombocytopenic purpura etc.), dose modification and management will follow the Manual “Pembrolizumab Program (MK-3475): Event of Clinical Interest Guidance Document”.

For non-immune-related hematological AEs (e.g. neutropenia, thrombocytopenia etc.) dose modification and management will follow Table 4 below. Determination of immune related versus non-immune-related etiology is at the investigator’s discretion.

For SJS, TEN and immune-mediated myocarditis, see the Investigator Brochure for management.

Recommendations to managing irAEs and any AEs not detailed in the Manual are provided in Table 5. (5.5.2)

For subjects who are receiving maintenance treatment, lenalidomide will be withheld before or at the same time of MK-3475 withhold at the investigator’s discretion. Determination of cause-effect relationship of AEs (lenalidomide versus MK-3475) is at investigator’s discretion.

Table 4: Dose Modification Guidelines for Non-Immune-Related Hematological Drug- Related Adverse Events

Discontinue Hold Timing for Dose/Schedule Subject (after Treatment restarting for restarting consultation Toxicity Grade (Y/N) treatment treatment with PI) Non-immune-related 1, 2, 3 No N/A N/A N/A Hematological Toxicity 4 Yes Toxicity May increase Toxicity does (e.g. neutropenia, resolves to the dosing not resolve thrombocytopenia, Grade 0-1 or interval by 1 within 4 weeks etc.) baseline week. of last infusion Permanent discontinuation should be considered for any severe or life-threatening event

5.4 Concomitant Medications/Vaccinations (allowed & prohibited) Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during the ongoing study. If there is a clinical indication for one of these or other medications or vaccinations specifically prohibited during the study, discontinuation from study therapy or vaccination may be required. The investigator/Institution should discuss any questions regarding this with the Merck. The final decision on any supportive therapy or vaccination rests with the investigator and/or the subject's primary physician. However, the decision to continue the subject on study therapy or vaccination schedule requires the mutual agreement of the Investigator, Merck, and the subject.

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5.4.1 Acceptable Concomitant Medications All treatments that the investigator considers necessary for a subject’s welfare may be administered at the discretion of the investigator in keeping with the BMT community standards of medical care. All concomitant medication will be captured in patient medical record including all prescription, over-the-counter (OTC), herbal supplements, and IV medications and fluids. If changes occur during the study period, documentation of drug dosage, frequency, route, and date may also be included on the CRF. Only the concomitant medications taken during any SAEs or ECI/ irAEs will be recorded on the Case Report Form (CRF).

All concomitant medications received within 28 days before the first dose of MK-3475 (or ~14 days prior to transplant) and 30 days after the last dose of MK-3475 should be captured in patient medical record.

Glucocorticoid up to an equivalent dose of prednisolone 30 mg/day for 5 days is allowed for the treatment of engraftment syndrome. See glucocorticoid dosing for suspected acute infusion reactions (see 5.5.1 and the Manual “Pembrolizumab Program (MK-3475): Event of Clinical Interest Guidance Document)) and immune-related adverse reactions (see 5.5.2, 5.5.3 and the Manual “Pembrolizumab Program (MK-3475): Event of Clinical Interest Guidance Document).

As stated above, any treatments, including systemic glucocorticoid, which the investigator considers necessary for a subject’s welfare may be administered at the discretion of the investigator in keeping with the BMT community standards of medical care.

Thus, inevitable systemic corticosteroid treatment for a subject’s welfare is NOT considered a protocol violation or deviation.

5.4.2 Prohibited Concomitant Medications Subjects are prohibited from receiving the following therapies not specified in the study protocol during the Study Treatment Period:

• Anti-multiple myeloma systemic chemotherapy or biological agents not specified in this protocol:

IMiDs (lenalidomide other than maintenance therapy specified in this protocol, thalidomide, pomalidomide), proteasome inhibitors (bortezomib, carfilzomib) and other new related targeted biologic agents.

• Glucocorticoids for any purpose should be avoided.

EXCEPT for the following conditions: o Engraftment syndrome as specified in this protocol o Acute infusion reactions as specified in Section 5.5.1 o Event of clinical interest / immune-related adverse events (ECI / irAEs) as specified in Section 5.5.2 and Section 5.5.3 o Adrenal insufficiency supplement with physiologic glucocorticoid dose at an investigator’s discretion

However, as stated above, any treatments, including systemic glucocorticoid, which the investigator considers necessary for a subject’s welfare may be administered at the discretion

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of the investigator in keeping with the BMT community standards of medical care. Thus, inevitable systemic corticosteroid treatment for a subject’s welfare is NOT considered a protocol violation or deviation.

• Sargramostin (Granulocyte/Macrophage-Colony Stimulating Factor: GM-CSF)

• Warfarin

• Immunotherapy not specified in this protocol

• Any chemotherapy not specified in this protocol

• Investigational agents other than MK-3475

• Radiation therapy

Radiation therapy to a symptomatic solitary lesion may be allowed after consultation with Investigator/Institution. Disease progression must be investigated accordingly.

• Live vaccines within 30 days prior to the first dose of trial treatment and while participating in the trial. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however intranasal influenza vaccines (e.g. Flu-Mist®) are live attenuated vaccines, and are not allowed.

Subjects who, in the assessment by the investigator, require the use of any of the aforementioned treatments for clinical management should be removed from the study. Subjects may receive other medications that the investigator deems to be medically necessary.

The Exclusion Criteria describes other medications that are prohibited in this study.

There are no prohibited therapies during the Post-Treatment Follow-up Phase.

5.5 Rescue Medications & Supportive Care

5.5.1 Supportive Care Guidelines Subjects should receive appropriate supportive care measures as deemed necessary by the treating investigator, including but not limited to, the common items outlined below:

1. Diarrhea: Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus).

In symptomatic subjects, standard post-transplant workup e.g. infectious etiologies must be performed, and if symptoms are persistent and/or severe, endoscopic evaluation should be

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considered before the diagnosis of MK-3475-related immunologic reaction is made. Information on how to identify and evaluate irAEs has been developed and is included in “the Manual “Pembrolizumab Program (MK-3475): Event of Clinical Interest Guidance Document” located in the Administrative Binder.

All subjects who experience diarrhea should be advised to drink liberal quantities of clear fluids. If sufficient oral fluid intake is not feasible, fluid and electrolytes should be replaced via IV infusion.

2. Nausea/vomiting: Nausea and vomiting should be treated aggressively, and consideration should be given in subsequent cycles to the administration of prophylactic antiemetic therapy according to standard institutional practice. Subjects should be strongly encouraged to maintain liberal oral fluid intake.

3. Infections: Subjects with a documented or suspicious infectious complication should receive oral or IV antibiotics or other anti-infective agents as considered appropriate by the treating investigator for a given infectious condition, according to standard institutional practice.

4. Immune-related adverse events: See Section 5.5.2 and the Manual “Pembrolizumab Program (MK-3475): Event of Clinical Interest Guidance Document in the administrative binder regarding diagnosis, report and management of adverse experiences of a potential immunologic etiology.

5. Acute Infusion Reactions: Acute infusion reactions, which may include cytokine release syndrome, angioedema and anaphylaxis, are different from allergic/hypersensitive reactions, although some of the manifestations are common to both AEs.

Signs and symptoms usually develop during or shortly after MK-3475 infusion and generally resolve completely within 24 hours of completion of infusion.

Signs/symptoms of acute infusion reactions may include: - Allergic reaction/hypersensitivity (including drug fever), rigors/chills, pruritus/itching, myalgia, urticaria (hives, welts, wheals) - Arthralgia (joint pain), fatigue (asthenia, lethargy, malaise) - Rash/desquamation - Bronchospasm; Cough; Dyspnea (shortness of breath) - Dizziness - Headache - Hypertension, hypotension, tachycardia - Nausea/ vomiting - Sweating (diaphoresis) - Tumor pain (onset or exacerbation of tumor pain due to treatment)

See the Manual “Pembrolizumab Program (MK-3475): Event of Clinical Interest Guidance Document for diagnosis, report and management of acute infusion reactions.

5.5.2 Supportive Care Guidelines for Events of Clinical Interest (ECI) and Immune-related Adverse Events (irAEs)

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An Event of clinical interest (ECI) of a potential immunologic etiology (irECIs) may be defined as an adverse event of unknown etiology, associated with MK-3475 exposure and is consistent with an immune phenomenon. irAEs may be predicted based on the nature of the MK-3475 compound, its mechanism of action, and reported experience with other immunotherapies that have a similar mechanism of action. Special attention should be paid to AEs that may be suggestive of potential irAEs.

An irAE can occur shortly after the first dose or several months after the last dose of treatment.

If an irAE is suspected, efforts should be made to rule out neoplastic, infectious, metabolic, toxin or other etiologic causes prior to labeling an adverse event as an irAE. Information on how to identify and evaluate irAEs has been developed and is included in the Manual “Pembrolizumab Program (MK-3475): Event of Clinical Interest Guidance Document located in the Administrative Binder.

Subjects who develop a Grade 2 or higher irAE should be discussed immediately with Investigator/Institution and Merck.

**For subjects who are receiving maintenance treatment, lenalidomide will be withheld before or at the same time of MK-3475 withhold at the investigator’s discretion. Determination of cause- effect relationship of AEs (lenalidomide versus MK-3475) is at investigator’s discretion.

Recommendations to managing irAEs not detailed elsewhere in the protocol or the Manual “Pembrolizumab Program (MK-3475): Event of Clinical Interest Guidance Document are detailed in Table 5.

Table 5: General Approach to Handling irAEs and any AEs NOT specified in the Manual “Pembrolizumab Program (MK-3475): Event of Clinical Interest Guidance Document”

irAE Withhold/Discontinue Managements

Grade 1 No action Provide symptomatic treatment.

Grade 2 Withhold until resolving to Consider systemic corticosteroids as per Grade Grade 1. 3, irAEs in addition to appropriate symptomatic treatment.

May increase dosing interval by 1 week (every 4 weeks) after resolving to Grade 1 or less.

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Grade 3 Withhold until resolving to Systemic corticosteroids are indicated in Grade 1. addition to appropriate symptomatic treatment.

Discontinue if unable to Prednisone 1-2 mg/kg/day or equivalent reduce corticosteroid dose to < 10 mg per day Add anti-inflammatory e.g. infliximab, if not improving in 48-72 hours. prednisone equivalent within 12 weeks of Steroid taper should be considered once toxicity. symptoms improve to Grade 1 or less and tapered over at least 4 weeks.

May increase dosing interval by 1 week (every 4 weeks) after resolving to Grade 1 or less.

Grade 4 Discontinue permanently Systemic corticosteroids are indicated

Methylprednisolone 125 mg IV or prednisone 1- 2 mg/kg/day or equivalent, then follow the ECI Guidance Document.

Add anti-inflammatory e.g. infliximab, if not improving in 48-72 hours.

5.5.3 Management Guidelines for Pneumonitis Subjects with symptomatic pneumonitis should immediately stop receiving MK-3475 and have an evaluation. The evaluation may include bronchoscopy with bronchoalveolar lavage to rule out other causes such as infection. Management, report and dose modification will follow the Manual “Pembrolizumab Program (MK-3475): Event of Clinical Interest Guidance Document”..

5.5.4 Diet/Activity/Other Considerations

1. Diet Subjects should maintain a diet according to institutional guidelines for autologous transplant, unless modifications are required to manage an AE such as diarrhea, nausea or vomiting.

2. Contraception In general, pregnancy is a contraindication for receiving high-dose melphalan and autologous transplant; however, becoming pregnant after transplant is not impossible in the first 6-12 months post-transplant.

MK-3475 may have adverse effects on a fetus in utero. Furthermore, it is not known if MK-3475 has transient adverse effects on the composition of sperm.

Non-pregnant, non-breast-feeding women of child-bearing potential may be enrolled 1) if they are willing to use 2 methods of birth control until 120 days after the planned last dose of MK-3475 or 2) if they are considered highly unlikely to conceive.

Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 37

Highly unlikely to conceive is defined as 1) surgically sterilized, or 2) postmenopausal (a woman who is ≥45 years of age and has not had menses for greater than 2 years will be considered postmenopausal), or 3) not heterosexually active for the duration of the study.

Subjects should start using birth control from study visit 1 (first dose of MK-3475 treatment) throughout the study period up to 120 days after the last dose of MK-3475 therapy.

The two birth control methods can be either 1) two barrier methods or 2) a barrier method plus a hormonal method to prevent pregnancy

The following are considered adequate barrier methods of contraception: diaphragm, condom (by the partner), copper intrauterine device, sponge, or spermicide.

Appropriate hormonal contraceptives will include any registered and marketed contraceptive agent that contains an estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or intramuscular agents).

Subjects should be informed that taking MK-3475 may involve unknown risks to the fetus (unborn baby) if pregnancy were to occur during the study.

In order to participate in the study subjects must adhere to the contraception requirement as described above for the duration of the study and during the follow-up period defined in the section 7.2.2 – “Reporting of Pregnancy and Lactation to the Investigator/Institution and to Merck”. If there is any question that a subject will not reliably comply with the requirements for contraception, that subject should not be entered into the study.

Subjects receiving standard lenalidomide maintenance therapy must strictly follow contraception requirement per lenalidomide program as a standard of care.

3. Use in Pregnancy If a subject inadvertently becomes pregnant while on treatment with MK-3475, the subject will immediately be removed from the study. The site will contact the subject at least monthly and document the subject’s status until the pregnancy has been completed or terminated. The outcome of the pregnancy will be reported to the Investigator/Institution and to Merck without delay and within 24 hours if the outcome is a serious adverse experience (e.g., death, abortion, congenital anomaly, or other disabling or life-threatening complication to the mother or newborn). The study investigator will make every effort to obtain permission to follow the outcome of the pregnancy and report the condition of the fetus or newborn to the Investigator/Institution and to Merck.

If a male subject impregnates his female partner the study personnel at the site must be informed immediately and the pregnancy reported to the Investigator/Institution and to Merck and followed as described above and in Section 7.2.2.

4. Use in Nursing Women It is unknown whether MK-3475 is excreted in human milk. Since many drugs are excreted in human milk, and because of the potential for serious adverse reactions in the nursing infant, subjects who are breast-feeding are not eligible for enrollment.

Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 38

5.6 Subject Withdrawal/Discontinuation Criteria Subjects may withdraw consent at any time for any reason or be removed from the study at the discretion of the investigator should any untoward effect occur. In addition, a subject may be withdrawn by the investigator if enrollment into the study is inappropriate, the study plan is violated, or for administrative and/or other safety reasons. Specific details regarding discontinuation or withdrawal are provided in Section 7.1.4.

Subjects who complete 9 doses of MK-3475 will be considered having completed the study treatment.

A subject must be discontinued from the study for any of the following reasons: • Current planned autologous hematopoieitic cell transplant does not occur. • The subject or legal representative (such as a legal guardian) withdraws consent. • Confirmed disease progression • Unacceptable adverse experiences as described. • Intercurrent illness that prevents further administration of treatment • Noncompliance with study treatment or procedure requirements • Investigator’s decision to withdraw the subject • The subject is lost to follow-up • The subject has a confirmed positive serum pregnancy test • Administrative reasons

The End of Treatment and Follow-up visit procedures are listed in Section 6 (Protocol Flow Chart) and Section 7.1.5 (Study Visit Requirements).

Evaluable subjects who received at least 2 doses of MK-3475 will have End of Treatment Evaluation (Table 8). They will have Follow-up visit and Survival Follow-up procedures per Table 8, starting 8 weeks after End of Treatment Evaluation.

Non-evaluable subjects who received less than 2 doses of MK-3475 will not have the “Efficacy Assessments” or the “Tumor Biopsies/Archival Tissue Collection/Correlative Studies” as parts of End of Treatment Evaluation (Table 8). They will have Follow-up visit and Survival Follow-up procedures per Table 8, starting 8 weeks after End of Treatment Evaluation.

Non-evaluable subjects who have never received MK-3475 will NOT have End of Treatment Evaluation or Follow-up visit or Survival Follow-up procedures per Table 8.

All subjects will be followed for disease status for at least 3 years after transplant (See Table 6: Study Flow Chart) or until disease progression, initiating a non-study multiple myeloma treatment (except maintenance therapy as specified in this protocol), withdrawing consent or becoming lost to follow-up. After documented disease progression each subject will be followed by telephone for overall survival until death, withdrawal of consent, or the end of the study, whichever occurs first.

5.7 Subject Replacement Strategy

The following subjects will be replaced:

Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 39

1. Subjects who were screened and signed consent but received less than 2 doses of MK-3475 (non-evaluable subjects). 2. Subjects who are poor adherence to protocol and regulatory requirements or who are lost to follow-up prior to the end-of-study evaluation after the completion of MK-3475 treatment 3. Quality or quantity of data recording is inaccurate or incomplete

5.8 Clinical Criteria for Early Study Termination

Early trial termination will be the result of the criteria specified below:

1. Quality or quantity of data recording is inaccurate or incomplete. 2. Poor adherence to protocol and regulatory requirements. 3. Incidence or severity of adverse reaction indicates a potential health hazard to subjects.

5.9 Plans to Modify or Discontinue the Development of the MK-3475

In the event of Merck decision to no longer supply MK-3475, ample notification will be provided so that appropriate adjustments to subject treatment can be made.

5.10 Definition of Endpoints

5.10.1 SAFTY ENDPOINTS

1. ENGRAFTMENT and GRAFT FAILURE

Neutrophil engraftment day will be defined as the first day of the 3 consecutive days (or of the 3 consecutive tests for >3 day-duration) of achieving an absolute neutrophil count (ANC) >500/uL.

Platelet engraftment day will be defined as the first day of the 2 consecutive days (or of the 2 consecutive tests for >2 day duration) of achieving platelet count >20,000/uL, without transfusion support.

Primary graft failure will be defined as the inability to maintain an ANC >500/uL AND a platelet count >20,000/uL, without transfusion support and without other causes, e.g. viral infection, other known myelosuppressive medication or multiple myeloma progression, in a subject who survives 35 days after transplant.

Secondary graft failure will be defined as a decline of ANC to <500/uL after having engrafted that is unresponsive to growth factors, without other causes, e.g. viral infection, other known myelosuppressive medication or multiple myeloma progression.

2. REGIMEN-RELATED TOXICITY [RRT] An RTT is defined as an adverse event (AE) that occurs during the period right after the first dose of MK-3457 (day 14 +/- 4) until 14 days thereafter (day 28 +/-4), and is considered to be a direct consequence and a related event as a result of the combination of conditioning chemotherapy,

Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 40

and MK-3475. 3. TREATMENT-RELATED MORTALITY [TRM] TRM is defined as any death due to the transplant procedure, including death attributable directly to MK-3475 therapy. Death due to, but not limited to, the following events are considered a TRM: general transplant complications (e.g. infection, graft failure), RRT and Event of Clinical Interest (ECI) and immune-related AEs (irAEs)..

5.10.2 EFFICACY ENDPOINTS

1. RELAPSE / PROGRESSION

See Appendix 13.3 for the definitions of Multiple Myeloma Response Criteria, including relapse/progression. 2. PROGRESSION-FREE SURVIVAL [PFS] PFS is defined as the period from transplant day 0 to the day of the first Progression /Relapse.

3. OVERALL SURVIVAL [OS] OS is defined as the period from transplant day 0 to the day of death from any cause.

5.10.3 CORRELATIVE STUDIES

The following correlative studies are planned; however, failure to obtain peripheral blood hematopoietic stem cell graft tissue and post transplant blood samples at specified time points is not a study violation as these studies are not primary endpoints.

5.10.3.1 Pre-transplant phenotypic analysis of autologous graft tissue

5.10.3.2 Quantitative ex vivo Immune Function Recovery Assays 1) Lymphocyte subset recovery in anti-PD-1 enhanced HDT/ASCT 2) Functional measurements of T cell subtypes and cytokine profiles 3) NK cell cytotoxicity

Table 6: Correlative Study: Medical College of Wisconsin Laboratory of Bryon D. Johnson, Ph.D.

Biomarker name Assay Tissue/Body Fluid Tested and Timing of Assay Lymphocyte content of autologous Flow cytometry: Quantify activated and Graft tissue: pre-transplant day 0 or graft pre-transplant effector CD4+ and CD8+ cells, NK cells, previously frozen samples and regulatory T and B cells.

Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 41

Table 7: Correlative Studies: University of Michigan Laboratory of Steven K. Lundy, Ph.D.

Biomarker name Assay Tissue/Body Fluid Tested and Timing of Assay Lymphocyte recovery in anti-PD-1 Flow cytometry: Quantify activated and PBMC: pre-chemotherapy, day 14 post- enhanced HDT-ASCT effector CD4+ and CD8+ cells, NK cells, transplant [before first dose of anti-PD-1] and regulatory T and B cells. and day 100±7 and day 182±7 post- transplant Functional T cell subtypes and cytokine Cytokine profiling: Intracellular IFN-α, PBMC: pre-chemotherapy, day 14 post- profiles IFN-γ (flow cytometry), cytokine release transplant [before first dose of anti-PD-1], spectrum (Luminex), TH subset day 100±7 post-transplant, and day 182±7 transcription factor profiling (Q-PCR) post-transplant

NK cell cytotoxicity Intracellular granzyme B (flow cytom), PBMC: day 100±7 post-transplant, and day flow cytometric analysis of tumor cell 182±7 post-transplant death

5.10.3.3 Sample collection

We will obtain heparinized (green top; approximately 15 mL total/sample) peripheral blood hematopoietic stem cell graft tissue sample on day 0 or previously frozen graft sample and peripheral blood samples approximately on day +14 [or before the first dose of MK-3475], day 100±7 post-transplant and at early termination, if any, or day 182±7 post-transplant from each patient for the flow cytometric study of immune recovery and ex vivo T cell function. NK cytotoxicity measurements will be performed on the day +100+7 and day 182±7 time points using an additional 15 mL/patient blood draw. [Schema]

Samples [a 15-30 mL extra blood draw each; limit to maximal volume allowed per Institutional Policy)] will be collected coincidently with routine daily blood draws on the patients during transplant admission and clinic visits. All University of Michigan samples will be processed on the day of collection. Additional samples received from the Medical College of Wisconsin will be shipped overnight on wet ice and processed within 24 hours of being drawn. Plasma will be banked and frozen for analysis of anti-PD-1 antibody titers and other parameters if indicated. Leukocytes will be isolated by Ficoll gradient centrifugation and used for phenotypic and functional analyses described below. Previously frozen graft samples will be shipped frozen.

5.10.3.4 Flow cytometry Lymphocyte repopulation in peripheral blood and analysis of the peripheral blood graft tissue specimens will be assessed by multi-color flow cytometry using the cell surface and intracellular markers. For surface marker only staining, 2×105 PBMC will be stained with each panel and 2×104 cells will be analyzed. Antibody panels are designed to include markers of activated T cells, as well as regulatory and cytotoxic T and B cell subsets. CXCR4 expression will be determined as a marker for bone marrow homing potential. For intracellular cytokine staining, 5×106 PBMC will be stimulated for 3 days with anti-CD3 and anti-CD28 with the addition of brefeldin A for the last 5 hours to stop cytokine release. Cytotoxic cells will be stimulated for 3 days with recombinant human IL-2 prior to staining for intracellular granzyme B and Fas ligand expression. Isotype control antibody staining will be used as control for non-specific binding of the intracellular markers.

5.10.3.5 Cytokine release Cytokine production by PBMC will be analyzed at all time points. Culture supernatants will be collected from anti-CD3 and anti-CD28 stimulated PBMC (1×106 cells/mL) after 5 days of culture.

Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 42

Released cytokines will be measured by Luminex Cytokine Human 10-Plex Panel (Life Technologies). This panel simultaneously quantifies GM-CSF, IFNg, IL-1b, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, and TNFa in a single sample.

5.10.3.6 Quantitative PCR + The relative presence of CD4 TH cell subsets (TH1, TH2, TH17, and Treg) in fresh 1 million freshly isolated PBMC will be determined at all time points using the Human T Helper Cell RT2 Profiler PCR Array (Qiagen-SABiosciences).[82] This array sensitively measures the mRNA levels of 84 genes involved in TH cell differentiation without need of ex-vivo stimulation.

5.10.3.7 Cytotoxicity assays Killer function of NK cells will be determined in patient samples collected on day 100+7 and day 182+7 post-transplantation by flow cytometry.[83] Human multiple myeloma target cell lines (U266 and RPMI-8226) will be cocultured with CalceinAM-FITC-labeled patient PBMC for 4 hours. At the end of the coculture, NK cytotoxicity will be measured by labeling apoptotic cells with 7AAD and AnnexinV-APC and analysis by flow cytometry.

5.10.3.8 Partnering PI experience and credentials:

The laboratory correlative studies will be performed in the laboratories of Steven K. Lundy, Ph.D. and Bryon D. Johnson, Ph.D.

Dr. Lundy is a Research Assistant Professor in the Department of Internal Medicine of the University of Michigan Medical School. Dr. Lundy has over 27 years of experience as a technician, trainee and faculty member working in the field of immunology research. He has a particularly high level of expertise in the cellular immunological assays outlined in this proposal. Dr. Lundy spent the earliest parts of his career performing chromium release assays to measure NK cell cytotoxicity of tumor target cells and mixed lymphocyte reactions. He has extensive experience in the cloning and functional characterization of human CD4+ and CD8+ T cells, as well as assays related to human prostate and lung cancer cell metastasis.[120,121] His doctoral work focused on TH cell death mediated by B cells in the S. mansoni worm egg granuloma model, with an emphasis on the role of Fas ligand-positive B cell subsets.[122,123] Dr. Lundy’s work continues to be focused on the interactions between killer lymphocytes and their targets.[124,125] His laboratory is well-equipped to compare the effects of treatment with anti-PD-1 antibodies on the phenotypes and functions of human T cells,[126] and the cytotoxic potential of NK cells in these patients. His laboratory is well-equipped to compare the effects of treatment with anti-PD-1 antibodies on the phenotypes and functions of human T cells,[127] and the cytotoxic potential of NK cells in these patients[128].

The Lundy laboratory does not have CLIA certification, and therefore, results will not be used for clinical diagnostics or for any purposes other than the research endpoints outlined in the protocol.

Dr. Johnson is a Professor in the Department of Pediatrics at the Medical College of Wisconsin in Milwaukee. His laboratory recently generated new data using an animal model that shows blocking PD-1-Ligand on myeloma cells can promote elimination of the myeloma cells during lymhodepleted state in animals that had just been treated with a low dose of whole body irradiation. He was a recipient of 2012 Senior Research Grant Award from the Multiple Myeloma Research Foundation.

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